Trial Of IRE in Cholangiocarcinoma (TOnIC): Phase II
Phase: PHASE2
Conditions: Cholangiocarcinoma
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York Awnue 
New York, New York 10065 
 
 
 
 
 
 
MSK PROTOCOL COVER SHEET 
Trial Of IRE in Cholangiocarcinoma (TOn/C): Phase II 
PrincipalInvestigator/Department: T. Peter Kingham, MD/Surgery 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York Awnue 
New York, New York 10065 
 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ........................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC .AIMS .................................................................. 4 
3.0 
BAC:KGROUND .AND RATION.Al..E ............................................................................. 4 
4.1 
OVERVIEWOF STUDY DESIGN/INTERVENTDN .......................................................... 7 
4.2 
Design ................................................................................................................ 7 
4.3 
Intervention .......................................................................................................... 7 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................ 7 
6.1 
CRITERIAFOR SUBJECT ELIGIBILITY .................................................................... 8 
6.2 
Subject Inclusion Criteria .................................................................................. 8 
6.3 
Subject Exclusion Criteria ..................................................................................... 9 
7.0 
RECRUITMENT PLAN ............................................................................................ 9 
8.0 
PRETREATMENT EV.ALUATION ................................................................................... 9 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................... 10 
10.0 
EV.Al..UATION DURING TREATMENT/INTERVENTION ..................................... 12 
11.0 
TOXICITIES/SIDE EFFECTS.............................................................................. 13 
12.0 
CRITERIAFOR THERAPEUTIC RESPONSE/OllTCOME ASSESSMENT ............... 14 
13.0 
CRITERIAFOR REMOVAi.. FROM STUDY ............................................................ 15 
14.0 
BIOSTATISTICS ................................................................................................. 15 
15.1 
RESEARCH  PARTICIPANT  REGISTRATION .AND RANDOMIZATION PROCEDURES16 
15.2 
Research Partcipant Registration ....................................................................... 16 
15.3 Randomization ............................................................................................... 17 
16.1 
DATAM.ANAGEMENTISSUES ...................................................................................... 17 
16.2 
Quality Assurance .................................................................................................... 17 
16.3 Data and Safety Monitoring ................................................................................... 17 
17.1 
PROTECTION OF HUMAN SUBJECTS ......................................................................... 18 
17.2 
Privacy ........................................................................................................ 18 
17.3 
Serious Adverse Event {SAE) Reporting .................................................................... 18 
18.0  INFORMED CONSENT PROCEDURES ..................................................................... 20 
19.0 
REFERENCES .................................................................................................... 21 
20.0 
APPENDICES ...................................................................................................... 23 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
1.0   PROTOCOL SUMMARY AND/OR SCHEMA 
 
Rationale: The majority of patients with perihilar cholangiocarcinoma (PHC) have locally advanced 
disease {LAD} upon presentation or exploratory laparotomy; for this reason, they are not suitable 
candidates for curative resection[1]. Additionally some of the patients develop locally advanced 
recurrence during their course of disease. Therefore, in most patients with this type of biliary tract 
cancer,only palliative concepts can beoffered.ERCPguided and/or percutaneous transhepatic biliary 
drainage offer the best survival, because in combination with sufficient drainage, reduction of tuma 
masses in the lumen of the bile duct was shown to prolong patient survival[2]. Effectiveness of 
photodynamic therapy (PDT) was investigated in two randomized controlled and a few controlled 
studies[3-8]. But these studies failed to prove efficacy with clear impact on clinical outcomes. 
Mlreover, PDT has not become part of normal clinical practice because it causes skin phototoxicity 
lasting for 3-4 weeks and requires technology not available at most centers. Other thermalablative 
methods, such as radiofrequency ablation, are affected by a heat-sink effect when tumors are located 
close to vascular structures, such as the liver hilum, which can limit effectiveness, and there are 
concerns with injuries to biliary and vascular structures in treating these areas. These limitations may 
be overcome by irreversible electroporation {IRE}, which is a non-thermal tissue ablation method that 
has been used to treat liver tumors in over 60 patients at MSK. By exposing cancer cells toa sufficient 
electric field byIRE, cell plasma membranesare disrupted and cells undergo apoptotic or necrotic cell 
death[9, 10]. Therefore,IRE is considered as non-thermal ablation technique and is currently applied 
to treat liver tumors where thermalablation techniques are contraindicated. 
Objective: This study will investigate the outcomes of IRE for the treatment of unresectable,locally 
advanced PHC.. 
Study design:A single center phase II study. 
 
Study population:20 patients withlocally advanced PHC deemed unresectable due to preoperatively 
determined primary tumor characteristics and/or distant lymph node metastases (N2} or due to 
discovery of unresectability on exploratory laparotomy. 
Mainstudy endpoints: 
 
The primary outcome is patency of biliary drainage. In patients with plastic percutaneous drains this 
is defined as ability to remove plastic biliary drains within 1.5 months of the IRE procedure without 
need for reinsertion of a drain or stent. For patients with metal stents in place the definition of patent 
biliary drainage is 4-months without cholangitis post IRE procedure. 
 
Secondaryoutcomesarethe success rateof completing IRE (defined as percentage of planned pulses 
completed}, complications, duration of hospital stay, quality of life, impact of IRE on post-procedural 
CT imaging and blood biomarker response,time between IRE and start of palliative chemotherapy, 
metal stent patency, progression-free and overall survival. Prolonged hospital stay is defined as 
hospital stay for morethan 10 days. The average length of stay for major liver procedures is 8 days. 
Patients with hilar cholangiocarcinomas often have biliary drains and stents so require extra care as 
inpatients after any procedure. Complications will be defined as patients experiencing a clinically 
relevant IRE-related complication within 30 days post-IRE, defined as CTCAE (version 5.0} grade 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
3 or higher complications requiring re-intervention, prolonged hospital stay, intensive careadmission, 
re-admissionor leading to mortality. 
Follow up: 30 days after intervention for the primary endpoint. For survivalendpoints, there is a 2-year 
followup. 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary objective: 
The primary objective of this study is to assess patency of biliary drainage. In patients with 
plastic percutaneous drains this is defined as ability to remove plastic biliary drains within 1.5 
months of the IRE procedure without need for reinsertion of a drain or stent. For patients with 
metal stents in place the definition of patent biliary drainage is 4-months without cholangitis 
post IRE procedure. 
 
Secondary objective: 
 
The secondary outcomes of interest are 
• Duration of hospital stay 
• Complications 
• Quality of life 
• Tumor response on CT imaging and blood biomarker response 
• Time between IRE and start of palliative chemotherapy 
• Duration of palliative chemotherapy 
• Progression-free and overall survival 
• Success rate of completing IRE (defined as percentage of planned pulses completed) 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Perihilar cholangiocarcinoma (PHC),also known as Klatskin tumor, is the most commontype 
of bile duct cancer, with an annual incidence of 1to 2 per 100,000 in Western countries. It 
arises at or near the confluence of the right and left main bile duct. Patients typically present 
with obstructive jaundice and are staged with cross-sectional imaging of the abdomen and 
chest. In the absence of metastatic disease, patients are eligible for resection with curative 
intent, which is the only treatment that confers a chance of long-term survival[11]. Five-year 
overall survival (OS) after resection varies from 13% to 40% across series with more than 100 
patients[12]. The poor 5-year OS reflects a high recurrence rate of 49 to 76% after curative 
intent resection of PHC [13]. Only 50% of the patients were suitable candidates for surgery 
due to unresectability at presentation and another 40% are found to have locally advanced or 
metastatic disease during exploratory laparotomy. In patients with disease ultimately deemed 
unresectable, approximately half of tumors are considered locally advanced because of 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
unreconstructable vascular involvement or extensive biliary involvement. Liver transplantation 
in these cases is only performed in a few experienced centers worldwide with strict selection 
criteria and extensive preoperative work-up including neoadjuvant treatment. Unfortunately, 
high dropout rates up to 30% prior to transplantation are reported. Systemic chemotherapy is 
the mainstay of treatment for patients who are not candidates for curative resection or 
neoadjuvant therapy followed by liver transplantation.Traditionally, the preferred regimen has 
been the combination of gemcitabine and cisplatin and offers a median progression-free 
survival of 8 months and overall survivalof 12 months[14].The recently released results fran 
the BILCAP randomized trial of adjuvant capecitabine compared to best supportive care 
showed an apparent lack of benefit in the hilar cholangiocarcinoma patients (HR 1.09; 95% Cl 
0.68, 1.71;ASCO 2018 abstract). Trials in patients with moreadvanced disease suffer from a 
lack of accrual of patients with locally advanced hilar cholangiocarcinoma, so we have to 
extrapolate from trials like BILCAP. 
The goals of palliative biliary drainage are to relieve jaundice, prevent cholangitis and liver 
failure, and improve quality of life [15]. Biliary stents are not without risk and have been 
associated with occlusion, migration, cholecystitis, and tumor ingrowth and seeding[16]. 
Successfulbiliary drainage has obvious palliative advantages to leaving patients undrained 
due to the morbidity of untreated cholangitis. In addition, in one randomized trialof plastic vs. 
metalstents, there was asurvival advantage with metal stents comparedto plastic stents (due 
tolonger patency rates) [17]."'1etal stents are a moredurable and cost-effective option as they 
have a patency superior to that of plastic stents, with patients requiring less frequent 
procedures (Table 1) [18]. IVorbidity related to stents can occur even within 30 days of 
placement (39% plastic stents and 12% metal stents) [19]. Although the overall prognosis of 
unresectable PHC is poor, patients with locally advanced PHC or lymph node metastases 
 
 
 
 
 
beyond the hepatoduodenal ligament have significant longer survival (14 to 16 months) 
compared to patients with organ metastases (3 to 5 months)[20]. 12% of these patients even 
survive for more than 36 months[20]. This particular subgroup of PHC patients with primary 
locally advanced disease may therefore benefit from ablative therapies that counteract tuma 
growth and potentially improve biliary stent patency and survival. In the past decade,several 
different ablative techniques like stereotactic body radiation therapy, photodynamic therapy 
(PDT), (intraductal) radiofrequency ablation {RFA), brachytherapy and microwave ablation 
have been investigated. Localtumor reduction by PDT in combination with stent therapy is 
effective for reducing cholestasis. For patients with unresectable hilar cholangiocarcinoma,two 
randomized studies and several controlled studies have shown an advantage in survivalover 
stenting alone, given improved stent patency[21]. Furthermore,some trials demonstrated a 
gain in Qol or in performance status[4-7]. But PDT has major limitations such as skin 
phototoxicity for 3-4 weeks due to the use of slowly degradable photosensitizers in PDT[22]. 
In addition, thermal ablative  modalities {i.e. RFA) are limited  by the disadvantages  of 
surrounding tissue heating causing strictures to bile ducts and thromboses to portal vein and 
Table 1.Time of patency (months) 
Plastic stents 
"'1etal stents 
P value 
Sanachan et al r171 
1.0 
3.0 
<0.0001 
Raiu et alr181 
1.9 
5.6 
<0.0001 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
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1275 York A-..enue 
New York, New York 10065 
 
 
 
 
hepatic artery branches and the heat-sink effect. This effect is caused by blood flow in 
surrounding vessels creating an area where optimal temperatures are not reached, leaving 
viable cancertissue in situ [23]. This is particularly challenging in PHC because of the typical 
location in the liver hilum near the portal vein and hepatic artery. Considering these limitations, 
there is a need to investigate new non-thermal ablative techniques in the treatment of locally 
advanced PHC. 
IRE is FDA approved for soft tissue ablation. Bile duct cancers are consideredsoft tissue.The 
most extensively studied organ for use of IRE has been the liver and the liver hilum, where 
delicate structures in the hepatoduodenal ligament preclude intervention using thermal 
ablation techniques. Demonstration of lack of significant acute injury to hepatic vessels and 
bile ducts by the early work of Lee et al [24] has now been corroborated by several authors 
with confirmed safety with up to 8 weeks of follow-up[25, 26].An overall complication rate of 
16% has been recently described in a meta-analysis[27]. /ls a comparison, in a review on 
hepatic RF ablation in 3,670 patients, the overall complication rate was 9%,with rates of 7%, 
10%, 10%, and 32% for percutaneous, laparoscopic, simple open, and combined open RF 
ablation[28]. 
In one study using serial computed tomography (CT) scanning, IRE lesions created around 
large hepatic veins showed minimal early narrowing, but with complete recovery over time and 
no evidence of late thrombosis or occlusion[26].IRE around hilar bile ducts similarly showed 
overall resistance to significant injury, with some ducts exhibiting, at worst, clinically 
insignificant late strictures [29].Three major studies have been published by ourgroup at MSK 
in the past about irreversible electroporation in perivascular or peribiliary hepatic malignant 
tumors [30-32]. Silk et al [32] evaluated biliary complications after IRE of 19 liver metastases 
in nine patients within 1 cm of the common,left, or right hepatic duct. One patient showed 
subsegmental bile duct prominence without increased bilirubin; this still existed after 11 
months, without progressive dilation or segmentalatrophy. Retrospective review of computed 
tomography images showed that one needle was placed in direct contact with the bile duct. 
Two other patients showed bile duct dilation with increased bilirubin, for which one required 
stent placement; both conditions appeared to be secondaryto tumor progression. Kingham et 
al [30] treated 28 patients with 65 tumors, of which most were located < 1 cm from a major 
hepatic vein or portal pedicle, similar to patients with PHC. The overall morbidity was 3%. 
Complications included 1intraoperative arrhythmia and 1postoperative portalvein thrombosis. 
There were no treatment-associated mortalities. At. median follow-up of 6 months, therewas 1 
tumor with persistent disease (1.9%) and 3 tumors recurred locally (5.7%)[30]. In the 
Netherlands, a phase VII feasibility studyof IRE in patients with advanced PHC (ALPACA-trial) 
was initiated this year[33]. A series of 26 patients with unresectable hilar cholangiocarcinoma 
was also recently published {IV'artin et al, Safety and efficacy of irreversible electroporation in 
the treatment of obstructive jaundice in advanced hilar cholangiocarcinoma. HPB, 2018 in 
press). This retrospective review compared these patients to 137 patients with unresectable 
hilar cholangiocarcinoma who did not undergo IRE.The median catheter free time in the IRE 
patients was 305 days (range 92-458 days). Of the 137 control patients, 80 (59%) had an 
admissionfor biliary drain infection,occlusion,or other catheter related problem. This bolsters 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
our hypothesis that IRE in patients with unresectable perihilar cholangiocarcinoma canprolong 
the stent patency and therefore prevent septic complications. In addition,only 2 of 26 patients 
had a grade 3 or higher complication,. 
 
The demonstration of tissue structure sparing in the many organs (especially in the liver) 
supports the relative safety of IRE, and bodes well for this technology's potential. However, 
several investigators have pointed out the lack of complete understanding of how best to 
optimize IRE treatments in a variety of tissues, healthy, and neoplastic. Altering the treatment 
parameters of the energy transmitted to the tissue may produce zones of IRE as well as zones 
that may be subjected to additional effects including thermal damage, especially in tissue 
immediately surrounding an electrode. As demonstrated by the work of Faroja et al, tissue 
temperatures exceeding protein denaturation can be achieved by manipulation of certain 
dosing parameters. Recent work also showed differences in imaging and histopathology 
effects as a function of distance from the IRE electrode, with an immediate perielectrode zone 
that appeared to have more coagulative changes in contrast to the expected non-coagulative 
IRE zone marked by congestion.Choi et al. showed potential damage to the bile duct mural 
architecture when the IRE electrodes were immediately adjacent to the ducts. As a safety 
precaution, placement of electrodes < 3 mm to centralbile ducts should be avoided. 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a prospective, single-center phase II study to look at the outcomes of\ IRE with the use 
of NanoKnife® system (AngioDynamics, Queensbury, NY) in patients with preoperatively 
diagnosed locally advanced, unresectable PHC due to vascular or lymph node involvement, 
or those with potentially resectable tumors (those that are expected to be fully resectable 
before surgery) that appear intraoperatively to be locally advanced or metastasized to N2 
lymph nodes at exploratory laparotomy. 
 
4.3 
Intervention 
The study will evaluate the outcomes of using IRE in patients with intraoperatively determined 
advanced unresectable PHC. The study will include data from 20 patients that have this IRE 
procedure performed as standard of care by hepatopancreatobiliary surgeonswith experience 
using  IRE. 
 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTICAGENTS 
 
The NanoKnife (AngioDynamics, Queensbury, NY) IRE device will be used in all patients. The 
device is cleared by the US Food and Drug Administration for use in ablating soft tissue.The 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
 
IRE device comprises a generator, a foot pedal, and 15- or 25-cm-long electrodes. The 
electrodes used to treatthese patients have atip length ranging from5 to 40 mm.This distance 
represents the active tip of the electrode and the remainder of the needle is insulated. The IRE 
device generates 1,500 to 3,000 V. Voltage is determined by a standard algorithm 
(AngioDynamics) that uses factors such as the intended size of the ablation zone,the number 
of probes, the distance between probes, and the length of the active electrode tip.[15] The size 
or shape of the tumor determines the number of electrodes used. 
 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
The study population consists of 20 adult patients who are diagnosed with locally advanced, 
unresectable PHC. Unresectability will be established either preoperatively, based on imaging 
and other preoperative testing, or intraoperatively in patients undergoing planned exploratory 
laparotomy. Patients will be recruited at the outpatient clinic. In cases of a planned exploratory 
laparotomy, patients will be asked to participate in the study in case disease is deemed 
unresectable during surgery. These patients will undergo IRE during the same operative 
session. Patients with unresectable tumors based on imaging at initial visit or preoperative 
workup, will be asked to participate in the study and receive IRE via laparotomy. Prior to 
surgery, biopsies will be taken to verify perihilar cholangiocarcinoma. Patients with resectable 
PHC, PHC eligible for liver transplantation or organ metastasized PHC at surgical exploration 
will be excluded. The subject exlusion criteria outlined below is evaluated per standard of care 
for the IRE procedure and as such is listed in this protocol. 
 
6.2 
Subject Inclusion Criteria 
 
In order to participate in this study, a patient must meet all of the following criteria: 
 
• 
e 18 years or older 
• Capable of providing written and oral informed consent in English 
Meets criteria for unresectable disease: 
• Locally advanced disease based onpreoperative work-up demonstratingthat the tumor 
is unresectable due to portal vein, hepatic artery, and/or bile duct involvement, 
insufficient hypertrophy response of the future liver remnant after portal vein 
embolization, or patients not able to tolerate major liver surgery 
 
• Found to be unresectable intraoperatively based on vascular, biliary, or lymph node 
(N2) involvement upon exploratorylaparotomy 
 
• Patients will be assessed for chemotherapy prior to treatment with IRE, but given the 
common problem of recurrent cholangitis, some patients will not be candidates for 
chemotherapy until after IRE is performed. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
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New York, New York 10065 
 
 
 
 
6.3 
Subject Exclusion Criteria 
 
• Locally advanced PHC eligible and accepted for liver transplantation evaluation 
• PHC with > 5 cm extension along the common hepatic duct or common bile duct on 
preoperative imaging or intraoperative ultrasound 
• Metastases to peritoneum, liver or other organs confirmed by percutaneous biopsy, 
staging laparoscopy or intraoperative frozen section 
• Lymph node  metastases beyond  N2 stations, confirmed by intraoperative  frozen 
sections or radiographic diagnosis 
• History of cardiac disease: 
• Congestive heart failure (NYHA class >2) 
• .Active Coronary Artery Disease (defined as myocardial infarction within 6 
months prior to screening) 
• Cardiac arrhythmias  requiring  anti-arrhythmic therapy  or pacemaker  (beta 
blockers are permitted) 
• Ally  implanted stimulation device (defined as implantable cardiac device and a 
pacemaker) 
• Uncontrolled hypertension (blood pressure must be 
160/95 mmHg at the time of 
screening on a stable antihypertensive regimen) 
• Uncontrolled infections (> grade 2 NCl-CTC, version 3.0) 
• Epilepsy 
• Both narrowing (sclerosis) of the main portalvein and a reduced diameter of either the 
common hepatic artery,celiac trunk or superior mesenteric artery of >50% 
 
 
7.0 
RECRUITMENT PLAN 
 
All patients will be recruited in outpatient clinic by one of our hepatopancreatobiliary (HPB) 
attendings (PK, WJ,JD,VB, MD, AW, KS). Full study information will be provided by the study 
physician or one of the investigators during the outpatient clinic appointment. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
Due to the nature of disease,patients with PHC undergo extensive pre-operative work-up (e.g., 
laboratory testing, CT or MR imaging, biliary drainage, liver function tests) prior to surgical 
exploration and potential portal vein embolization. In the present study, patients that will 
undergo open IRE during exploratory laparotomy will have undergone these preoperative 
work-up procedures as standard of care. Additionally Quality of life will be assessed duringthe 
pre-treatment visit  using the  Functional Assessment of Cancer Therapy-Hepatobiliary 
instrument (FACT-Hep). FACT-Hep is a 45-item self-report instrument designed to measure 
QoL in patients with hepatobiliary cancers. It comprises the FACT-General (FACT-G) and the 
hepatobiliary subscale (Hep). The FACT-G consists of 27 items that measure 4 domains of 
well being in cancer patients: physical well being (PWB), social/family well being (SWB), 

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IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
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1275 York A-..enue 
New York, New York 10065 
 
 
 
 
functional wellbeing (FWB), and emotionalwell being (EWB).The instrumentemploys a Likert- 
type format (0 "not at all" to 4 "very much"). Lower total scores reflect lower Qol.The FACT- 
G score is a total of the subscalescores. The FACT-G has demonstrated internalconsistency, 
score stability, reliability, and validity  [34-39]. The Hep is a reliable and validated disease- 
specific subscale consisting of  questions  relating  to  pruritus, jaundice, and  drainage 
catheters[40,41).Patients will not be replaced if they do not complete these questionnaires. 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
Preoperative  biliarydrainage 
Biliary drainage for malignant hilar strictures or masses is a complex procedure requiring 
considerable skill and experience. Candidates for IRE who initially present with potentially 
resectable PHC undergo preoperative biliary drainage as part of the standard preoperative 
work-up. In the present study, the exact approach of biliary drainage (i.e.endoscopically or 
percutaneously, specified liver segments, unilateral or bilateral) prior to surgery is decided by 
surgeon. A metal biliary stent is not considered a contraindication for IRE as long as a no- 
touch technique is pursued (i.e. IRE electrodes are not in contact with the metalstent). 
Antibiotic  prophylaxis 
 
Antibiotic prophylaxis will be administered according to the MSKCC's protocol prior to biliary 
drainage and IRE.Patients will receive one 2g dose of Cefotetan IV, 30-60min prior to surgery. 
The same antibiotic will be used for the treatment of cholangitis (2g Cefotetan rv every 12 
hours). In case of a patient allergy to Cefotetan, patients will receive Clindamycin/Gentamicin 
as alternative antibiotic treatment. 
lntraoperative IRE procedure 
 
Antibiotic prophylaxis is administered prior to the operation. During exploratory laparotomy, 
resectability of the tumor is assessed by the attending surgeon. When the tumor appears 
resectable, a resectionwill be performed.In case of non-nodal (extra)hepatic dissemination of 
the tumor, no procedure will be performed. In both cases the patients will be excluded frcrn 
this study. Only when the tumor appears  non-resectable, but non-metastasized, an IRE 
procedure will be performed.The IRE procedure will be performed under ultrasound guidance 
by the attending surgeon. 
NanoKnife® device settings 
The NanoKnife® IRE device (AngioDynamics, Queensbury, NY) will be used in this study in 
normalclinical fashion.This means the machine will be configured to deliver 90 pulses lasting 
one microsecond each,high-voltage (1500-3000 V) direct current (25-45 A) electrical pulses. 
Before administering the 90 one-microsecond therapeutic pulses, a test pulse at 270 V is 
delivered. Typically, 90 pulses will be delivered in 9 sets of 10 pulses between paired unipolar 
electrodes, with an exposed tip of 1.5-2.0 cm. The voltage setting for each electroporation will 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
 
be determined by the distance between each pair of electrodes and will be aimed at 1500 
V/cm, with the intent to generate at least 1000 V between electrodes. The electrodes will be 
placed in and around the tumor under ultrasound guidance according to the manufacturer's 
guidelines, aiming at a macroscopically complete ablation with a 5 mm margin,with the inter- 
electrode distances 10-24 mm and a maximum angulation between electrodes of 15°. The 
predicted treatment zone will be automatically calculated using the NanoKnife generator 
softwareaccording to a system-based protocol that takes into account the exact position of all 
electrodes. The number of probes used for ablation is dependent on tumor size. If the lesion 
islarger or has a different shape than the area that one set of probes can cover (according to 
manufacturer's guidelines), multiple ablations will be performed, until the whole tumor area is 
ablated. Number of probes, number of probe replacements (per probe) due to unsatisfactory 
placement, number of pulses (for each pair of electrodes), probe length, space between 
probes, pulse voltage (amplitude,Volt), pulse length (µsec),pulse interval(ms)will be carefully 
noted.All complications (cardiac and non-cardiac) will be carefully registered and monitored). 
Specific attention will be paid to the placement of electrodes close to bile ducts as previous 
research demonstrated that biliary strictures may occur whenneedles are placed within 3mm 
of the bie ducts[29,42]. 
Post IREtreatrrent 
 
Patients will be monitored on the recovery and surgical wards daily, according to current 
medicalpractice. Patients with endoscopic or percutaneous plastic drains will be evaluated for 
definitive metal stents (fully-, partially- or uncovered self-expanding metal stents) or removal 
of drains if obstruction appears to be treated by IRE in all patients through an endoscopic or 
percutaneous approach atleast 7 days after the IRE procedure. This 7-day window is built in 
to avoid manipulation of the biliary tree immediately after IRE. Bile ducts to atrophic liver lobes 
will not be drained. Following exploratory laparotomy and open IRE, patients will undergo 
treatment in an enhanced recovery program. Patients will be monitored on the recovery and 
the surgicalward daily and discharged when fully recovered from the laparotomy,according 
to current medicalpractice. 
Generaltreatment 
 
Patients with advanced PHC generally receive optimal palliative chemotherapy and adequate 
biliary drainage with metal stenting.In the current study,patients undergo local ablative therapy 
of the tumor. As it may be difficult to distinguish local IRE-related effects on computed 
tomography scans or MRI from residualtumortissue or tumor progression, it was decided that 
all patients in the current study will be proposed to receive palliative chemotherapy. 
Palliative chemotherapy 
 
All patients will be seen by the medical oncologist at l\llSKCC prior to intraoperative IRE is 
performed, and palliative chemotherapy will be discussed.Patients will be offered optimal 
palliative chemotherapy according to medical oncology preferences. Palliative chemotherapy 
is not mandatory to participate in the trial,as some patients will not be eligible due to ongoing 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
cholangitis. Palliative chemotherapy post procedure is preferably started within 6 weeks after 
IRE when the patient has recovered from definitive metal biliary stent placement. The start of 
chemotherapy may be postponed inthe event of IRE-or biliary drainage-related complications. 
However, delay of start to chemotherapy is not expected. In fact, we suspect that patients will 
be likely have a better chance of being treated with chemotherapy and for a longer duration of 
time,due to stent patency. 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Data collection prior and during hospital admission 
 
Prior to the procedure we will collect: 
 
Baseline parameters: Demographics, tumor characteristics and serum markers that will be 
routinely collected are: age, sex, comorbidity,body mass index (BMI), tumorsize,tumor growth 
pattern, arterialorvenous vascular involvement,nodal status, cancer antigen (CA) 19.9, lgG4, 
albumin, C-reactive protein (CRP), leukocytes. If lgG4 level is normal at baseline further 
measurements are not necessary and will therefore not been included in the follow up. 
 
 
During the hospital stay,we will collect data onserum liver enzymes and inflammatory 
parameters (WBC, CRP). 
Follow up 
 
During follow up,after discharge, patients will be seen in the outpatient clinic, as is routine 
practicefor post-operative/post-procedural patients, for clinical evaluation and laboratory 
testing of liver enzymes, inflammatory parameters (WBC, CRP), Albumin and tumor markers 
(CA 19.9). 
In this study, patients will also be seen in the outpatient clinic at 2 weeks, 4 weeks, and 
approximately 6, 12, and 24 months, as is routinely performed for clinical follow-up currently. 
Laboratory tests obtained at visits after the first post-procedurevisit will be determined by the 
surgeon. 
The date of disease progression is defined as the date of CT scan onwhichthe firstsuspected 
lesion is defined. 
Quality of life will be assessed at the initial clinic visit, initial post-operative visit (2 weeks fran 
surgery), and at subsequent post-operative visits .±. 1 month from 3,6,9,12, and 24 months 
following the IRE procedure. The Functional Assessment of Cancer Therapy-Hepatobiliary 
instrument {FACT-Hep) will be used. If patients are unable to complete the questionnaires at 
the desginated visits for any reason,they will be offered the option of returning the QOL via 
mail. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
 
 
 
 
 
Imaging 
 
CT and rvRI scans used for routine clinical care will be used for this protocol. If patients are 
receiving chemotherapy, a pre-chemotherapy scanwill be obtained 4-6 weeks post procedure, 
as per standard clinicalpractice. If no chemotherapy is planned a scan at 4-6 weeks will be 
clinically appropriate to assess disease progression,treatment response, and stent patency. 
Scans every 4-6 months will be used in patients on and off chemotherapy to evaluate for 
disease progression, which is consistent with current practices for routine management of 
patients with PHC. Tumor response is defined as a loss of enhancement for hypervascular 
tumors and as alack of persistent tumor rim enhancement for hypovascular tumors on contrast 
imaging studies.  Persistent disease  is defined  as  residual  tumor enhancement  on the 
posttreatment imaging studies, and local recurrence is defined as an enhancing tumor within 
1cm of an ablation zone. 
In order to diagnose complications such as biliary leakage, intra-abdominal abscesses or 
bleeding, ultrasound and CT are used. When disease progression is expected, a CT is 
performed to confirm (or refute) the clinical suspicion.This procedure is consistent with normal 
clinicalstandards. 
Follow up ofsubjects withdrawn from treatment 
 
Patients withdrawn from treatment will not have undergone the IRE procedure and are 
therefore considered not to have participated in this study.These subjects will receive normal 
follow-up outside this study. 
 
 
11.1 TOXICITIES/SIDE EFFECTS 
 
In the postoperative period we will observe for known IRE-specific toxicities. These include 
(expected frequency in parenthases): 
• Hemorrhage, requiring blood transfusion,radiological, or surgicalintervention (3%) 
• Hepatic abscess requiring surgery, drainage, or antibiotic therapy alone (5%) 
• Biliary stenosis requiring stent placement, bile leakage requiring radiological or 
surgicalintervention  (4%) 
• Portalhypertension, portobiliary fistula, hemobilia, thrombosis of hepatic artery or 
portal vein (3%) 
• Hepatic infarction (3%) 
• Large biloma (above 5cm) (3%) 
• Liver failure (1%) 
• Cardiac arrest, heart attack, cardiac arrhythmia during IRE (1%) 
• Diaphragmatic paresis (lesion in liver segment VIII) {1%) 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
 
Expected adverse events associated with the delivery of strong electric pulses are cardiac 
arrhythmias and severe muscle contractions. To prevent these events, pulses are generally 
delivered in the refractory period of the heart and with deep muscle paralysis [43]. Despite 
electrocardiographic synchronization,passage of high-voltage pulses into the body can still 
cause conduction disturbances in the heart. In a recent published meta-analysis by Scheffer 
et al., cardiac arrhythmias occurred in 4 of 194 patients (2%), but they were all atrial 
arrhythmias that resolved spontaneously or within 24 hours after therapy[27]. With the 
administration of muscle relaxants, no uncontrolled muscle contractions were reported[30, 32, 
44-48]. Only Thomson et al. reported a transient increase in systolic blood pressure in all 
patients directly after IRE (20-30 mm Hg), which normalized spontaneously[46]. 
Retrospective comparison showed that numerous liver capsule punctures during IRE did not 
cause subcapsular hemorrhage and pain after hepatic IRE and RF ablation showed similcr 
moderate pain intensity with comparable amounts of self-administered pain medication[49]. 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOMEASSESSMENT 
 
The primary endpoint is biliary drainage patency. This will be measured as a marker of 
therapeutic response. Biliary drainage patency in patients with metal stents is defined as the 
period between IRE treatment and stent occlusion or patient death. Occlusionof the stent is a 
clinical event.  This  is defined  as  recurrent jaundice with  cholestasis, cholangitis  (fever, 
increase in serum bilirubin,leukocytosis), stent failure that leads to replacement of a stent, or 
need toinsert a new drain or stent within 4 months. Biliary drainage patency failure in patients 
that with plastic drains is defined as patients that cannot have plastic drain removed within 1.5 
months of the IRE. 
 
The patients and caregivers are told about the symptoms of cholangitis and are asked to 
contact our hospital immediately in case of signs of obstruction. If stent obstruction is 
suspected, ERCwill be performed and stents are changed if necessary. 
 
Tumor response will not be evaluated in this trial by imaging via RECIST criteria as Klatskin 
tumors are difficult to measure as they are growing along the biliary tract. 
 
Subjective evaluation of the ablation zone to determine the appearance of an IRE associated 
ablation zone in the hilar area will be performed on postoperative scans. 
Persistent disease is defined as residual tumor enhancement on the first post-treatment 
imaging study, and local recurrence is defined as an enhancing tumor within 1 cm of an 
ablation zone. 
Ni a secondary endpoint we are measuring overall survival. If there is a response to our 
treatment, we would expect there may be a longer overall survival. 
Response on blood biomarker is defined as decrease of blood marker by >20% from the pre- 
treatment value. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
 
 
 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
Subjects can leave the study at any time for any reason if they wishto do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. Patients who withdraw before 120 days due to complications will be 
counted as failures for the patency objective.Patients who withdraw before 30 days will be 
counted as having experienced a complication for the purposes of the secondary objective. 
14.1 
BIOSTATISTICS 
 
The primary objective of this study is to assess biliary drainage patency after IRE treatment of 
hilar cholangiocarcinoma.In patients with plastic percutaneous drains this is defined as ability 
to remove plastic biliary drains within 1.5 months of the IRE procedure without need for 
reinsertion of a drain or stent. For patients with metal stents in place the definition of patent 
biliary drainage is 4-months without cholangitis post IRE procedure. 
Wewill enroll 20 patients. f\fean patency is approximately 1.5 months for plastic stents and 4 
months for metal stents. Assumingan exponential distribution time to failure, we extrapolate 
that the patency rate at 1.5 months for plastic stents and at 4 months for metalstents will 
approximately be 37% and we will use this number as our historical control rate. If 10 or 
more of the 20 patients we plan to enroll display patency (at 1.5 months for plastic and 4 
months for metal stents) then we will recommend IRE for further study.This decision rule has 
8% Type Ierror and 12% Type II error for distinguishing between patency rates of 37% and 
65%. 
The secondary outcomes of interest are: 
• Safety will be assessed by determining the proportion of patients experiencing a 
clinically relevant complication within 30 days post-IRE, defined as CTCAE (version 
5.0) grade 3 or higher complications requiring re-intervention, prolonged hospital stay, 
intensive careadmission,re-admission or leading to mortality.After accruing the first 8 
patients, we will do an interim analysis of safety. If 4 or more of these 8 patients 
experience a grade 3 complicationwithin 30 days post-IRE (as defined above) then the 
study will stopfor lack of safety.A 30 day observation window will follow after the eigth 
patient is enrolled. If one patient in the first 8 patients has a grade 4 or 5 complication 
the study will be halted. If none of these conditions are met then the we will accrue 
another 12 patients. If 6 or fewer of the total group of 20 patients have a grade 3 
complication we will conclude that the safety endpoint has been met. This safety 
monitoring rule has an 81% chance of stopping the study early for safety concerns if 
the true probability of complications is 35%. If there is a death during the 30-day post- 
procedure period the study will be halted to examine the relationship of death to the 
procedure. Wewill examine the cause of death for all 30-day deaths and determine if 
it could be related to the procedure. If the death can possibly be related to the 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
 
procedure then the protocolwill be stopped.To continue with the protocol after a death, 
we will submit to IRB all the documentation related to the ascertainment of cause of 
death and describe how it cannot be related to the IRE procedure. 
• Duration of hospital staywill summarizedwith median, range and quarti es. 
• Quality of life will be summarized by average subscale scores at each visit and 
change from previous visit will also be reported by the same summarystatistics. 
• Tumor response on CT imaging and blood biomarker response will be reported as a 
binomial proportion with a 95% confidence interval. RECIST criteria cannot be 
applied to Klatskin tumors as they are radiographically difficult to assess. This instead 
will be a subjective evaluation of the ablation zone to determine the appearance of an 
IRE associated ablation zone in the hilar area. This is currently unknown. 
• Time between IRE and start of palliative chemotherapy will summarized with median, 
range and quartiles 
• Duration of palliative chemotherapy will summarized using Kaplan-fv1eier statistics 
• Progression-free and overall survival will summarized using Kaplan-l'v'leier statistics 
• Success rate of completing IRE reported as a binomial proportion with a 95% 
confidence interval 
Expected accrual rate, accrual duration, and study duration 
 
Our anticipated accrualrate is approximately 1 patient per month. This accrualrate is based 
on analyzis of potentially eligible patients seen at our Outpatient Clinic in the last 2 years 
(2016 and 2017). Thus, it should take approximately 1.5 years to accruethe 20 patients 
needed for the trial. Allowing for 2 months of follow-up to obtain the primary endpoint on the 
last patient enrolled and 4 months to assemble, analyze and interpret the data the totalstudy 
duration is projected to be at most 2 years. Patients who consent to the procedure but do not 
have it will be considered a screenfailure. They will be replaced by another patient and their 
questionnaire data will be removed from the study. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
ResearchParticipant  Registration 
 
Confirm eligibility as defined in the sectionentitled Criteria for Patient/Subject Eligibility. 
 
Obtaininformed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
The indMdual signing the Eligibility Checklist will confirm whether or not the participant is 
eligible to enroll in the study. Study staff are responsible for ensuring that all institutional 
requirements necessaryto enroll a participant to the study have been completed.See related 
ClinicalResearch Policy and Procedure #401 {Protocol Participant Registration). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York Awnue 
New York, New York 10065 
 
 
 
 
 
All participants must be registered through the Clinical TrialManagement System 
(CTMS).The completed signature page of the written consent/RA or verbal script/RA, a 
completed Eligibility Checklist and other relevant documents must be uploaded into CTMS. 
15.2 
Randomization 
 
Not applicable 
 
 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A ClinicalResearch Coordinator (CRC) will be assigned to the study. The responsibilities of 
the CRC include project compliance,patient registration,eligibility  confirmation,data 
collection,abstraction and entry, data reporting, sample de-identification, regulatory 
monitoring, problem resolution and prioritization and coordination of the activities of the 
protocol study team. The data collected for this study will be entered into a REDCap 
database on a secureserver. 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of consent and registration data. Routine data quality reports will be generated to assess 
missingdata and inconsistencies. Accrual rates and extent and accuracy of evaluations and 
follow-up will be monitored periodically throughout the study period and potential problems 
will be brought to the attention of the study team for discussionand action.The principal 
investigator will maintain final responsibility for data during the study and during the final 
analysis of data. Breaches of protocol, problems with informed consent, or discrepancies in 
data accuracywill be reported to the IRB as required. 
16.3 
Data and Safety Monitoring 
 
The Data and Safety M>nitoring (DSM) Plans at l\llemorial Sloan Kettering Cancer Center 
were approved by the National Cancer Institute  in September 2001.The plans address the 
new policies set forth by the NCI in the document entitled "Policy of the National Cancer 
Institute for Data and Safety M>nitoring of ClinicalTrials" which can be found at: 
http://www.cancer. gov/cli nical trial s/conducting/dsm-gui deli nes .The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data 
and Safety M>nitoring Plans can be found on the MSKCC Intranet at: 
https://one.mskcc.org/sites/pub/clinresearch/Documents/MSKCC%20Data%20and%20Safet 
y%20M>nitoring%20Plans.pdf 
 
There are severaldifferent mechanisms bywhich clinicaltrials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff  
education on clinical research QA) and departmental procedures for quality control,plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinicaltrials programs. The committees: Dataand Safety Monitoring Committee (DSMC) for 
Phase Iand II clinicaltrials, and the Data and Safety Monitoring Board (DSMB) for Phase Ill 
clinicaltrials, report to the Center's Research Counciland Institutional Review Board. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York Awnue 
New York, New York 10065 
 
 
 
 
16.3 Regulatory Documentation 
 
Prior to implementing this protocolat l'v1SK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB}. Therewill be one protocol 
document an each participating site will utilize that document. 
 
 
17.1 
PROTECTIONOF HUMMI SUBJECTS 
 
The responsible investigator will ensure that this study is conducted in agreement with the 
Declaration of Helsinki (Tokyo, Venice, Hong Kong,Somerset West and Edinburgh 
amendments). The study will seek in every way to protect the rights of humansubjects. The 
potential risks will be discussed indetail with the patients. Potential side effects as outlined 
above will be discussed withthe patients. No patient will be required to participate in the 
study and participation or lack of participation will not affect the patient's subsequent careor 
treatment. The cost of getting the IRE procedure is not paid by the study sponsor. sothe 
patient or their insurance company will have to pay for this. Participation will be purely 
voluntary and subjects will not be reimbursed for participation in the study.Throughout the 
study, patient confidentiality will be maintained. No results of the study will be presented or 
discussed in a fashion that will allow identification of a particular patient in the study.All 
adverse events (AEs} will be fully disclosed to the IRB in a timely fashion as required. 
17.2 
Privacy 
 
MSK's Privacy Office may allow the use and disclosureof protected health information 
pursuant to a completed and signed ResearchAuthorization form. The use and disclosureof 
protected health information will be limited to the individuals described in the Research 
Authorization form. A ResearchAuthorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB}. 
 
The consent indicates that individualized de identified information collected for the purposes of this 
study may be shared with other qualified researchers. Only researcherswho have received approval 
from MSK will be allowed to access this information which will not include protected health 
information,such as the participant's name,except for dates. It is also stated in the Research 
Authorization that their researchdata may be shared with other qualified researchers. 
 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in "1NY of the following outcomes: 
• Death 
• A life-threatening adverse event 
• An adverse event that results in 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 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York Awnue 
New York, New York 10065 
 
 
 
 
 
• Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or participant and may require medicalor surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soonas the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant's last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocoltreatment must be reported. 
 
Please note: Any SAE that occurs prior to the startof investigational treatment/intervention 
and is related to a screeningtest or procedure (i.e.,a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submissionto the HRPP office per 
IRB SOP RR-408 'Reporting of Serious Adverse Events', the SAE report must be submitted 
within 5 calendar days of the event. Allother SAEs must be submitted within 30 calendar 
days of the event. 
 
 
The report should contain the following information: 
 
• The date the adverse event occurred 
• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment(s) 
• If the AE was expected 
• Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant's condition 
o Indication if the participant remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
 
For IND/IDE protocols: The SAE report should be completed as per above instructions. If 
appropriate,the report will be forwarded to the FDA by the IND Office 
 
17.2.1 
 
Any additional SAE reporting information required by the sponsor or drug supplier should be 
included in this section. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York Awnue 
New York, New York 10065 
 
 
 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocoland study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time.All participants must sign an IRS/PB-approved consent 
form indicating their consent to participate. This consentform meets the requirements of the 
Code of Federal Regulations and theInstitutional Review Board/Privacy Board of this Center. 
The consent formwill  include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. .Alternatives to the proposed study. (This will include avai able standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professionalwill 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRBInformed Consent, all patients mustagree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York Awnue 
New York, New York 10065 
 
 
 
 
19.0 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York A-..enue 
New York, New York 10065 
 
 
 
 
 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 18-489 A(4) 
Approvaldate:04-Nov-2020 
Memorial Sloan Kettering cancer Center 
1275 York Awnue 
New York, New York 10065 
 
 
 
 
 
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20.0 
APPENDICES 
 
Appendix A:. FACT-Hep