PRAMA (Prostate Resection After Microwave Ablation) MRI/Ultrasound Fusion Guided Transperineal Targeted Microwave Ablation for Prostate Cancer
Phase: NA
Conditions: Prostate Carcinoma
Sponsor: University of Southern California

 
 
Local Protocol #: 4P-23-1 
Protocol Title: MRI/Ultrasound fusion guided Transperineal 
Targeted Microwave Ablation for Prostate Cancer 
Protocol version date: 6/16/2023 
 
ClinicalTrialsgov #: NCT06128525 
 
 
 

  
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR. 
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as 
authorized in writing by the study sponsor. 
 
PRAMA (Prostate Resection After Microwave Ablation) 
 
MRI/Ultrasound fusion guided Transperineal Targeted Microwave Ablation for Prostate Cancer 
 
 
Principal Investigator: 
Andre Abreu 
 
 
 
 
Department of Urology  
 
 
 
 
1441 Eastlake Ave. STE 7416 
 
 
 
 
(323) 865-3000  
 
 
 
 
(323) 865-2700 
 
 
 
 
andre.abreu@med.usc.edu 
 
Co-Principal Investigator: Inderbir S. Gill 
 
 
 
 
Department of Urology  
 
 
 
 
1441 Eastlake Ave. STE 7416 
 
 
 
 
(323) 865-3000  
 
 
 
 
(323) 865-2700 
 
 
 
 
inderbir.gill@med.usc.edu 
 
Co-Investigator(s):  
Manju Aron 
 
 
 
 
Department of Pathology 
 
 
 
 
manjuaro@usc.edu 
 
 
 
 
 
Biostatistician: 
 
Jie Cai 
 
Study Drug:  
 
NA 
 
IND Number:  
 
NA 
 
Funding Source:  
Funding from Koelis (Medical device company) 
 
Initial version:  
 
06/16/2023 
Amended: 
 
 
 
 
Research Office:                 CLINICAL INVESTIGATIONS SUPPORT OFFICE (CISO) 
                                                    1441 Eastlake Avenue, Room 7310E 
                                                     Los Angeles, California 90089-9177 
                                                           Telephone (323) 865-0451 
Email: ciso.clinical@med.usc.edu 
 
 
 
 
 
 
 
Signature Page 

  
UNIVERSITY OF SOUTHERN CALIFORNIA/KENNETH NORRIS, JR. 
COMPREHENSIVE CANCER CENTER AND HOSPITAL 
 
 
 
 
CONFIDENTIAL 
This material is the property of the University Of southern California/ Norris Comprehensive Cancer Center. Do not disclose or use except as 
authorized in writing by the study sponsor. 
 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: Andre Luis De Castro Abreu 
 
 
 
PI Signature: _____________________________ 
 
Institutional Name: USC Institute of Urology  
 
Date: ____________________ 
 

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i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .............................................................................................. 1 
STUDY SCHEMA ............................................................................................................. 3 
STUDY SUMMARY .......................................................................................................... 5 
1.0 BACKGROUND AND RATIONALE ........................................................................... 8 
1.1 
Disease Background ................................................................................................ 8 
1.2 
The use of TMA (Study Agent): opportunities and challenges ................................ 8 
1.3 
Rationale for this study ............................................................................................. 9 
1.4 
Goal of Proposed Study ......................................................................................... 11 
1.5 
Hypothesis .............................................................................................................. 12 
1.6 
Study Overview ...................................................................................................... 12 
2.0 STUDY OBJECTIVES .............................................................................................. 12 
2.1 
Primary Objectives ................................................................................................. 13 
2.2 
Secondary Objectives ............................................................................................ 13 
2.3 
Descriptive Objectives ............................................................................................ 13 
2.4 
Primary Endpoints .................................................................................................. 13 
2.5 
Secondary Endpoints ............................................................................................. 13 
2.6 
Descriptive Endpoints  ........................................................................................... 13 
3.0 PATIENT ELIGIBILITY ............................................................................................. 13 
3.1 
Inclusion Criteria ..................................................................................................... 14 
3.2 
Exclusion Criteria ................................................................................................... 14 
4.0 TREATMENT PLAN ................................................................................................. 14 
4.1 
Treatment Dosage and Administration .................................................................. 14 
4.2 
Toxicities and Dosing Delays/Dose Modifications ................................................. 15 
4.3 
Concomitant Medications/Treatments ................................................................... 16 

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4.4 
Other Modalities or Procedures ............................................................................. 17 
4.5 
Removal of Patients from Protocol Therapy .......................................................... 17 
4.6 
Duration of Follow Up ............................................................................................. 17 
4.7 
Patient Replacement .............................................................................................. 17 
5.0 STUDY PROCEDURES ............................................................................................ 17 
5.1 
Screening Phase and Baseline Procedures .......................................................... 17 
5.2 
Randomization ....................................................................................................... 18 
5.3 
Treatment Procedures ........................................................................................... 18 
5.4 
Follow-up Procedures ............................................................................................ 21 
5.5 
Study Calendar ....................................................................................................... 23 
6.0 MEASUREMENT OF EFFECT ................................................................................. 25 
7.0 ADVERSE EVENTS .................................................................................................. 25 
7.1 
Experimental Therapy ............................................................................................ 25 
7.2 
Adverse Event Monitoring ...................................................................................... 26 
7.3 
Definition ................................................................................................................ 26 
7.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting ............... 28 
7.5 
Reporting Requirements for Adverse Events ......................................................... 28 
7.6 
Unblinding Procedures For Blinded and Randomized trials ................................ 299 
7.7 
Monitoring Rules for Safety .................................................................................. 299 
8.0 DEVICE INFORMATION ........................................................................................... 30 
9.0 CORRELATIVES/SPECIAL STUDIES ..................................................................... 31 
10.0 STATISTICAL CONSIDERATIONS ....................................................................... 31 
10.1 
Summary of Design ................................................................................................ 31 
10.2 
Justification of Trial Design. ................................................................................... 32 
10.3 
Primary Objective Statistical Considerations ......................................................... 32 
10.4 
Secondary Objective Statistical Considerations .................................................... 32 

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iii 
10.5 
Descriptive Objective Statistical Considerations .................................................... 32 
10.6 
Sample Size and Patient Accrual ........................................................................... 32 
10.7 
Data Analyses Plans .............................................................................................. 33 
10.8 
Reporting and Exclusions ...................................................................................... 34 
11.0 STUDY MANAGEMENT ......................................................................................... 34 
11.1 Conflict of Interest ..................................................................................................... 34 
11.2 
Institutional Review Board (IRB) Approval and Consent Process ......................... 34 
11.3    Required Documentation (for multi-site studies) .................................................... 35 
11.4 
 Registration Procedures ........................................................................................ 35 
11.6   RECORDS AND DATA SUBMISSION ................................................................... 35 
11.7  Data Management and Monitoring/Auditing ............................................................ 36 
11.8  Adherence to the Protocol ...................................................................................... 38 
11.9      Record Retention ................................................................................................. 39 
11.10    Obligations of Investigators .................................................................................. 39 
12.0 REFERENCES ........................................................................................................ 39 
13.0 APPENDICES ......................................................................................................... 42 

________________________________________________________________________ 
1 
LIST OF ABBREVIATIONS 
 
 
ADC 
apparent diffusion coefficient 
ADT 
androgen deprivation therapy 
AE 
adverse event 
AS  
active surveillance 
BP 
blood pressure 
CDC 
Clavien Dindo classification 
CEUS 
contrast enhanced ultrasonography 
CISO 
Clinical Investigations Support Office 
CRO 
Clinical Research Organization 
DCE 
dynamic contrast enhanced 
DSMC 
Data and Safety Monitoring Committee 
DWI 
diffusion weighted images 
eCRF 
Electronic Case Report Form 
EPIC 
Expanded Prostate Cancer Index Composite 
FDA 
The U.S. Food and Drug Administration 
FT 
focal therapy 
GCP 
Good Clinical Practice 
H&E 
hematoxylin and eosin 
HIFU 
high intensity focused ultrasound 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
ICU 
intensive care unit 
IIEF 
International Index of Erectile Function 
IND 
Investigational New Drug Application 
IPSS 
International Prostate Symptom Score 
IRB 
institutional review board 
ISUP 
International Society of Urological Pathology 
IV 
intravenous 
mpMRI 
multiparametric magnetic resonance imaging 
MRI 
magnetic resonance imaging 
NA 
not applicable 
NADH 
nicotinamide adenine dinucleotide hydrogen 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NCI 
National Cancer Institute 
OR 
operation room 
PCa 
prostate cancer 
PIRADS 
Prostate Imaging Reporting & Data System 
PRAMA 
Prostate Resection After Microwave Ablation 
PSA 
prostate specific antigen 
ROI 
region of interest 
RP 
Radical prostatectomy 
SAE 
Serious Adverse Event 
TMA 
Targeted Microwave Ablation 

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2 
TRUS 
transrectal ultrasonography 
TTC 
Triphenyltetrazolium chloride 
US 
Ultrasound 
USC 
University of Southern California 
 

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3 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
TARGETED MICROWAVE ABLATION (TMA) and RADICAL PROSTATECTOMY 
(RP) PHASE  
(A-B performed under the same anesthesia) 
A) Transperineal TMA ablation guided by KOELIS Trinity® MRI/US fusion system 
B) RP + pelvic node dissection immediately after TMA 
Figure 1. Study schema for immediate resection part 
 
HISTOLOGICAL CORRELATION (Whole-mount step-sectioned RP specimen) with 
C) Predictive ablation charts of the manufacturer, providing estimations of treatment 
effect dimensions for different microwave input power, time and energy 
D) Localization of the predicted ablation after 3D reconstruction of the prostate (“3D 
map”) on the KOELIS Trinity® system 
 
SCREENING PHASE/ INCLUSION CRITERIA 
Men with PCa, diagnosed by MRI prostate and MRI/Ultrasound (MRI/US) fusion 
prostate biopsy with KOELIS Trinity®, who have selected radical prostatectomy (RP) 
as their treatment (n=15).  
First 5 participants undergo microwave ablation and immediate prostatectomy. 
Following 10 participants undergo microwave ablation and 1 month delayed resection. 
 
Post operative day (POD) 10 (±5) 
days 
FOLLOW-UP PHASE 
E) Patient follow-up post TMA and RP  
a. for AE assessment 
 
 
COMPLETION PHASE 
F) Patient follow-up 1 month post RP  
a. for AE assessment 
b. for PSA measurement 
c. for functional outcome assessment 
G) This marks study completion. 
POD 30 (±10 days) 
First 5 participants 

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4 
STUDY SCHEMA continued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TARGETED MICROWAVE ABLATION (TMA) PHASE  
A) Transperineal TMA ablation guided by KOELIS Trinity® MRI/US fusion system 
 
HISTOLOGICAL CORRELATION (Whole-mount step-sectioned RP specimen) with 
F) Predictive ablation charts of the manufacturer, providing estimations of necrosis 
dimensions for different input power, time and energy 
G) Localization of the predicted ablation after 3D reconstruction of the prostate (“3D 
map”) on the KOELIS Trinity® system 
H) Imaging correlates with post TMA MRI 
 
SCREENING PHASE/ INCLUSION CRITERIA 
Men with PCa, diagnosed by MRI prostate and MRI/Ultrasound (MRI/US) fusion 
prostate biopsy with KOELIS Trinity®, who have selected radical prostatectomy (RP) 
as their treatment (n=15).  
First 5 participants undergo microwave ablation and immediate prostatectomy. 
Following 10 participants undergo microwave ablation and 1 month delayed resection 
 
POD 30 (±5 days) 
Following 10 participants 
Follow up Phase 2  
C) Patient follow-up post TMA and prior to RP 
iii) for mpMRI prostate 
iv) for AE assessment 
v) for functional outcome assessment 
vi) PSA 
 
Post TMA operative day (POD) 
10 (±5) days 
FOLLOW-UP PHASE 1 
B) Patient follow-up post TMA 
i) 
for AE assessment 
ii) for functional outcome assessment 
RADICAL PROSTATECTOMY (RP) PHASE 
D) MRI/TRUS fusion TP PBx with the patient under general anesthesia – 
immediately prior to RP, under the same anesthesia. 
E) RP + pelvic node dissection  
 

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5 
 
 
STUDY SCHEMA continued 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY SUMMARY 
Title 
PRAMA (Prostate Resection After Microwave Ablation) 
MRI/Ultrasound fusion guided Transperineal Targeted Microwave 
Ablation for Prostate Cancer 
Short Title 
PRAMA (Prostate Resection After Microwave Ablation) 
Protocol Number 
 
Phase 
Phase I 
Methodology 
Clinical Trial 
Study Duration 
One and a half year 
Study Center(s) 
USC Institute of Urology 
Primary Objective and 
related endpoint 
- Feasibility of transperineal targeted microwave ablation 
(TMA) of an MRI-identified index prostate tumor in patients 
with prostate cancer and eligible for radical prostatectomy. 
 
 The ablated area on the radical prostatectomy specimen 
assessed by viability tissue staining (TTC).    
 
COMPLETION PHASE 
J) Patient follow-up 1 month post RP  
i) 
for AE assessment 
ii) for PSA measurement 
iii) for functional outcome assessment 
K) This marks study completion. 
POD 60 (±10 days) 
Figure 2. Study schema for delayed resection part 
FOLLOW-UP PHASE 3 
I) 
Patient follow-up post TMA 
i) 
for AE assessment 
ii) for functional outcome assessment 
 
POD 40 (±5 days) 

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6 
                                 
Secondary Objectives 
and related endpoints 
- KOELIS Trinity ability to safely plan and guide treatment 
needles and ablations in the prostate index lesion 
 
 Number and severity of device- and procedure-related 
adverse events 
 TMA procedure duration: probe-in probe-out time, ablation 
time 
 Comparison between the ablation location in the prostate 
as seen in the KOELIS 3D reconstruction of the prostate 
(“3D Map”) and the ablation location observed histologically 
on the prostatectomy specimen 
 
- Impact of treatments on functional outcomes and quality of 
life 
 
 Change in urinary functions between baseline and each 
follow-up visit, using IPSS score and uroflowmetry   
 Change in erectile functions between baseline and each 
follow-up visit, using IIEF-5 score Change in quality of life 
between baseline and each follow-up visit, using EPIC-26 
score  
 
- Predictability of Medwaves Avecure microwave ablation 
charts   
 
 Correlation between the treatment effect dimensions 
measured histologically on the prostatectomy specimen 
resected immediately or 1mo after TMA, compared to the 
predictive ablation charts provided by the manufacturer. 
 Evaluation of the treatment parameters to induce the cell 
destruction without causing collateral damage 
 
- Predictability of post microwave ablation mpMRI 
   
 Correlation between the treatment effect dimensions 
measured histologically on the prostatectomy specimen 
resected 1 mo after TMA, compared to the post ablation 
dimensions measured on the mpMRI done prior to RP. 
 
Number of Subjects 
15 men with possible extension to more interventions                       

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7 
Diagnosis and Main 
Inclusion Criteria 
• 
Male  
• 
Index lesion visible on multiparametric MRI 
confirmed by targeted transperineal biopsies 
using KOELIS Trinity® 
• 
Having a diagnosis of prostate cancer (Gleason 
score ≤8) 
• 
Prostate size ≤ 150 cc 
• 
Patient suitable for IV sedation or general 
anesthesia and focal targeted microwave 
ablation 
• 
Having elected to undergo RP as treatment of 
choice  
• 
Ability to understand and the willingness to sign 
a written informed consent 
• 
Free, informed, and written consent, dated and 
signed before the enrollment and before any 
exam required by the trial 
Study Product(s), 
Dose, Route, Regimen 
A TMA ablation will be performed during each intervention. 
Duration of 
administration 
NA 
Reference therapy 
NA 
 
 
Statistical 
Methodology 
For practical considerations, the expected total number of study 
participants is 15 patients. This number may be extended in case 
further ablation parameters need to be tested.  
An analysis is planned to determine TMA delivery protocol 
(number of ablations, energy output, and time needed to ablate 
one MRI-visible lesion).  
 
We will assess the correlation between the treatment effect 
dimensions measured histologically on the prostatectomy 
specimen resected immediately or 1mo after targeted microwave 
ablation, compared to the predictive ablation charts provided by 
the manufacturer. 
We will report theablated area on the radical prostatectomy 
specimen assessed by viability tissue staining (TTC) on all fully 
evaluable patients. 

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8 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Prostate cancer (PCa) is the second most common cancer in men, with approximately 
1,400,000 men diagnosed and 375,000 who died of it worldwide in 2020 [1]. Most 
diagnosed Pca are localized and will never become aggressive during a patient’s 
lifetime.  
 
A great proportion of these men would benefit from enrolling in active surveillance (AS), 
which consists of monitoring with repeated biopsy and follow-up, and forgo any definitive 
treatments. Although AS has oncologic outcomes comparable to those of definitive 
treatments for low-risk disease patients [2]–[9], only ~40% of patients elect this modality 
due to perceived uncertainty about the aggressiveness of the tumor [10][11]. Further, 
within 5 years of initiating AS, over 35% of those who choose this starting therapy 
discontinue it in favor of definitive treatment. Therefore, most men with localized Pca still 
overwhelmingly elect to undergo treatment, whether it is radical prostatectomy (RP) 
surgery, radiation or androgen deprivation therapy (ADT), which can have a significant 
negative impact on their quality of life [12]–[14].  
 
Therefore, there is a great need for minimally invasive focal therapies (FT) that might 
allow patients to achieve the same benefits as of whole-gland therapies (RP, radiation) 
while avoiding the quality-of-life consequences of these definitive treatments. In order for 
these focal therapies to be successful, For focal therapy to succeed, requirements are 
an accurate localization of its geographic location, preferably with data-recall capability, 
and precise delivery of a cytocidal energy under image guidance [15] 
 
Moreover, non-invasive approaches to monitor disease eradication post-treatment need 
to be validated as well. In the recent past, several technologies and approaches have 
been developed that offer the possibility to do focal treatment of the prostate. In this 
study, we are focused on validating the use of targeted microwave ablation (TMA) for 
focal guided and targeted ablation of prostate cancer. 
 
1.2 
The use of TMA (Study Agent): opportunities and challenges 
FT including High Intensity Focused Ultrasound (HIFU) or cryosurgery have emerged as 
promising approaches that could achieve similar oncological results compared with 
whole-gland treatments, with the benefit of reduced morbidity and superior functional 
outcomes. 
 
Of particular concern are reports of the substantial rate of ‘in-field’ positive biopsies after 
“technically-successful” post FT (up to 12-35%) [14],[16]–[21]. Moreover, a small study 
reported a higher than expected number of viable cancer cells in post-FT RP specimens. 
Thus, there is an unmet need with optimal targeting and ablation capabilities. 
 
Microwave ablation is one of the ablation therapies that induces cell death by damaging 
cellular membrane or intracellular-structure membrane, as well as by denaturing and 
coagulating structural proteins and eradicating the local blood flow. This ablation method 
is used as a curative treatment option for renal cancers, liver cancers, and lung cancers 
[22]–[25]. So far, only a few studies investigated targeted microwave ablation for Pca 

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9 
[26][27][28]. However, there is no study evaluating TMA area with human RP specimen 
histology. Therefore, the optimal TMA delivery protocol has not been well investigated. 
 
When performing focal thermal ablation therapy such as cryoablation and HIFU, high 
blood flow adjacent to the ablated area may prevent effective ablation [29]–[31]. It is 
known as heat-sink effect. Previous studies reported microwave can rapidly generate 
high energy and ablate tissues in less time with limited heat-sink effect, and the volume 
of the microwave area can be predictable and repeatable [32],[33]. Compared to existing 
ablative technologies, the main advantages of microwave include higher intra-tumoral 
temperatures, larger tumor ablation volumes, faster ablation time, better intraoperative 
visualization and treatment monitoring, an improved convection profile, and less 
procedural pain [33].  
 
Targeting of the microwave to a given anatomic location within the prostate is currently 
possible given the advances in real-time MRI-TRUS image-fusion technology, which 
allows “highly accurate” tissue targeting and ablation. Although HIFU is one of the FDA-
approved focal ablation treatment technology for prostate cancer and performed 
worldwide, TMA has several advantages over HIFU. TMA is easier to position, since the 
TMA antenna is directly placed in the tumor and moves with tumor, even if the tumor 
shrinks with the ablative treatment. In addition, while HIFU treatment plans must avoid 
treatment beams passing through critical structures, such as urethra or prostatic 
calcifications, TMA can freely target the cancerous lesions even located in anterior of 
these critical structures [33].  
 
Surgical planning using 3D ultrasound and real-time monitoring of the ablation would 
thus preserve key anatomical landmarks. The Organ-Based Tracking (OBT®) patented 
technology would provide a 3D prostate model to facilitate real-time navigation-guided 
ablation and accurate mapping of the treatment zones, as well as automatically 
recalibrating the MRI/US fusion throughout the exam. 
 
Therefore, we believe TMA can be a treatment option for MRI-TRUS fusion biopsy 
proven Pca. 
 
1.3 
Rationale for this study 
Optimal FT modality to balance prostate cancer control and functional preservation is 
needed. However, current FT shows the substantial rate of recurrence from the ablated 
area. It may be partially due to the heat-sink effect. The existing literature and our own 
clinical experience with patients failing FT and subsequently undergoing salvage robotic 
RP has raised real-life concerns of the clear possibility of inaccurate targeting and 
inadequate ablation with current FT modalities, leaving behind residual cancer cells 
[16]–[21]. This problem is compounded by the fact that there are no studies that report 
on the validity of using existing tools to monitor FT success after treatment or shortly 
after, other than monitoring PSA and doing repeat biopsies. Therefore, current FT-
treated patients may go many months without knowing their treatment has failed. 
 
Microwave is known to be able to ablate tissues immediately and homogeneously with 
limited heat-sink effect and short ablation times based on previous studies for other 
organs [32],[33]. Therefore, microwave is a promising energy source for Pca treatment.  

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10 
TMA for Pca has been studied in the recent years and has shown an excellent safety 
profile and promising oncological outcomes[26][27][28]. However, to date no study has 
been performed to evaluate TMA with radical prostatectomy specimen histology 
immediate post-ablative resection.  . 
To establish TMA as effective FT option for Pca from oncologic and functional 
perspective, optimal TMA protocol should be identified. 
 
Important unanswered questions about the feasibility and efficacy of TMA include:  
1) Does an TMA-intended lesion accurately mirror the actual histologically-
confirmed tissue destruction in man? 
2) Are there skip-lesions of viable tissue within a ‘well-created’ TMA lesion? 
3) What is the optimal TMA protocol (i.e. ablation sessions, output energy, and 
ablation time) to acquire sufficient tissue ablation? 
4) How safe is TMA intra/post operatively?  
5) Can multiparametric MRI as contemporary imaging modality accurately confirm 
the completeness of TMA-induced Prostate tissue treatment effect at the histologic 
level? 
 
Definitive data attesting to the precision of TMA at the Pca tissue level are critical, as 
well as data documenting the most adequate treatment parameters to achieve such 
precision. Such fundamental, prostate tissue-level data in the human are lacking. To 
date, no published human studies have reported spatial thoroughness of TMA prostate 
tissue kill as correlated with contemporary imaging and histology to assess and predict 
tissue destruction; nor have TMA technologic parameters been directly correlated with 
thoroughness of human prostate tissue kill. 
 
The critical barrier to solve this problem is the ability to thoroughly examine the whole 
prostate gland in relatively close proximity to TMA ablation, timed appropriately to 
measure the relevant changes induced. Analyses should be soon enough before the 
ablated tissue starts to undergo fibrotic atrophy and shrinkage, as these would invalidate 
accurate comparison between imaging versus histologic measurements (e.g. salvage 
RP many months after TMA would not accomplish this, and it would also result in worse 
clinical outcomes for the patient due to peri-prostatic scarring involving the 
neurovascular bundles and sphincter). 
 
A Method, named as Triphenyltetrazolium chloride (TTC) staining, for assessing lethal 
thermal tissue injury is available which rely on the functional status of cellular enzymes 
and mitochondrial energy production to produce differential staining between thermal 
tissue necrosis and adjacent untreated viable tissue. The dehydrogenase enzymes 
assessed by this staining method are essentially within the mitochondria and utilize 
NADH/NADPH as electron donors to promote redox reactions. This viability stains use 
members of the tetrazolium family as their chromogen (stain colorant). The 
dehydrogenase enzymes and their cofactors (NADH and NADPH) reduce the colorless 
tetrazolium molecule into a colored formazan pigment (viable tissue). Following a 
thermal treatment, tissues with resultant denatured cellular enzymes and/or disrupted 
mitochondrial cofactor production will be unable to convert tetrazolium to its colored form 
and remain their native color (non-viable tissue) [34]. We adapt TTC staining to assess 
the location and extent of a treatment’s ablation/thermal effect within the prostate.  The 
use of TTC staining does not limit subsequent histologic prostate evaluation which is 
essential for optimal patient standard of care.  
 

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11 
When performing and evaluating viability stains, timing of the staining procedure is 
important. On the other hand, TTC staining should not be performed less than 2 hours 
from completion of the hyperthermic ablation. This post-treatment period allows for any 
residual enzyme and cofactor activity to fully cease and limits the risk of false positive 
staining. Thus, TTC staining should be performed more than 2 hours following the 
ablation and within 6 hours from tissue excision from the patient. This strict time frame is 
a rationale of the current ablation and immediate resect study protocol. 
 
In order to evaluate the feasibility of TMA in more practical setting, further analyses 
should be delayed long enough post-TMA treatment to allow tissue changes of 
irreversible thermal damage to set in. In this setting, we evaluate the ablation effect on 
histology using HE staining instead of TTC staining. This delayed resection allows us to 
evaluate short term safety of TMA and predictivity of post ablation mpMRI. It may also 
allow us to identify potential histological elements occurring after TMA, such as fibrosis 
or scar tissue.  
 
In this way, we will safely evaluate the optimal TMA protocol based on the first 5 cases, 
and will evaluate the practical feasibility of TMA using the following 10 cases. 
 
We do not anticipate pre-surgical TMA will cause any significant technical difficulties 
during the performance of RP.  Ablate and early resect studies have been performed 
after focal prostate ablation (HIFU, electroporation) with no reporting of adverse patient 
outcomes [35],[36]. Additionally, salvage (delayed) radical prostatectomy, years after 
failure of whole gland ablation, which are arguably much more challenging, is not an 
uncommon procedure offered at many centers [37],[38]. In fact here at USC, we have 
safely performed many (>100) salvage prostatectomies. 
 
Our proposed, prospective, “ablate & resect” trial will uniquely solve this problem while 
addressing the existing barriers. Recent advances in Pca imaging and targeted biopsy 
allow us to comprehensively address this problem. By definitively answering each of the 
above-listed five questions, our proposal will add novel scientific knowledge about 
tissue-level effects of prostate TMA in man; will for the first time corroborate these data 
with contemporary imaging and biopsy; will potentially improve the technical capability 
and delivery of TMA for Pca application; and thereby impact clinical practice for men 
desiring treatment for non-metastatic Pca.  
 
If successful, our study will have important clinical implications. It will definitively 
document whether TMA creates clinically reproducible targeted, irreversible destruction 
of prostate tissue in the human. This will be confirmed with the gold-standard of step-
section RP histology and TTC staining. Such tissue-level data is the first of its kind in the 
field.  If we are successful, a multicenter prospective study could be implemented to 
further validate our findings.  
 
1.4 
Goal of Proposed Study  
Our overall goal is to assess the feasibility of the TMA procedure by measuring its 
efficacy with the gold standard method (radical prostatectomy histological evaluation), its 
precision using the MRI/US guidance with organ-based tracking technology, and its 
safety with procedure- and device-related adverse events. 

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12 
1.5 
Hypothesis 
There are two main hypotheses: 
1) The microwave energy can safely kill prostate cancer cells in the treated area, 
eradicating evidence of prostate cancer  
2) The use of MRI/US image-fusion targeted biopsies technique with OBT-Fusion® 
allows a safe and precise guidance of a therapeutic needle in the area to be treated that 
was determined pre-operatively. 
1.6 
Study Overview 
We propose to conduct a comprehensive single institution ‘ablate and resect’ trial on 
Targeted Microwave Ablation (TMA) in patients undergoing robotic RP. Briefly, we will 
recruit patients with localized Pca undergoing RP as their treatment of choice. 
Immediately or 1 mo before performing RP, we will ablate the prostate with focal TMA. 
TMA treatment parameters will be chosen according to the manufacturer data and will 
be visualized in 3D using an MRI/US image-fusion platform (KOELIS Trinity®). After the 
prostatectomy we will study the entire prostate so that we can determine the rate of 
TMA-induced cell death. We will use a histologic step-sectioning approach to process 
the prostate that will allow us to correlate 1:1 the histology with imaging. The results of 
our study will provide answers to the following important questions.  
 
Important question #1: Is TMA effective in eradicating all prostatic tissue and prostate 
cancer cells within the ablated area? 
Important question #2: Can TMA be safely and precisely delivered to an index lesion of 
the prostate using the KOELIS Trinity® platform? 
Important question #3: Do TMA predictive treated areas dimensions correlate with 
ablated area as determined by histological changes measured via TTC staining post-
TMA on the prostatectomy specimen?  
Important question #4: What are the best TMA parameters to achieve maximum cell 
kill without causing collateral complications? 
Important question #5: How accurately post TMA MRI predict the treated area’s 
dimensions correlate with ablated area as determined by histological changes. 
Important question #6: What are the MRI findings after TMA and how the MRI 
correlates to histology on prostate biopsy and RP specimen? 
Important question #7: What is the perioperative AE after TMA? 
Important question #8: What is the feasibility and safety of RP after TMA in case of 
ablation failure? 
 
A total of 15 patients will be enrolled who will be identified from patients who have 
elected to undergo RP as their definitive treatment for PCa.  
Immediately prior to RP surgery, 5 patients will undergo TMA with one ablation in the 
prostate index lesion. 
One month prior to RP surgery, following 10 patients will undergo TMA with one ablation 
in the prostate index lesion. 
The number of patients included may be extended considering the need to evaluate 
different treatment parameters (still according to manufacturer dat. 
  
2.0 
STUDY OBJECTIVES 

________________________________________________________________________ 
13 
2.1 
Primary Objectives 
To determine the feasibility of transperineal targeted microwave ablation of an 
MRI-identified index prostate cancer in patients undergoing radical 
prostatectomy. 
2.2 
Secondary Objectives  
• 
KOELIS Trinity ability to plan and guide treatment needles and ablations in 
the prostate index lesion 
• 
Impact of treatments on functional outcomes and quality of life 
• 
Predictability of Medwaves Avecure microwave ablation charts 
• 
Predictability of post microwave ablation mpMRI 
2.3 
Descriptive Objectives 
NA 
2.4 
Primary Endpoints 
The ablated area on the radical prostatectomy specimen assessed by viability 
tissue staining (TTC).    
 
2.5 
Secondary Endpoints  
• 
The intra/post-operative safety of the targeted microwave ablation (number 
and severity of device- and procedure-related adverse events,  
• 
TMA procedure duration: probe-in / probe-out time, ablation time 
• 
Comparison between the ablation location in the prostate as seen in the 
KOELIS 3D map and the ablation location observed histologically on the 
prostatectomy specimen 
• 
The change in urinary functions between baseline and each follow-up visit, 
using IPSS score and uroflowmetry   
• 
The change in erectile functions between baseline and each follow-up visit, 
using IIEF-5 score 
• 
The change in quality of life between baseline and each follow-up visit, using 
EPIC-26 score  
• 
The correlation between the treatment effect dimensions measured 
histologically on the prostatectomy specimen resected after TMA, compared 
to the predictive ablation charts provided by the manufacturer 
• 
The correlation between the treatment effect dimensions measured 
histologically on the prostatectomy specimen resected one month after TMA, 
compared to post TMA dimensions measured on the pre-RP mpMRI. 
• 
Evaluation of the optimal treatment parameters to maximize the cell 
destruction without causing collateral damage. 
 
2.6 
Descriptive Endpoints 
NA 
 
3.0 
PATIENT ELIGIBILITY 

________________________________________________________________________ 
14 
Eligibility waivers are not permitted. Subjects must meet the inclusion and exclusion 
criteria to be registered to the study. Study treatment may not begin until a subject is 
registered. 
3.1 
Inclusion Criteria 
3.1.1 Adult men diagnosed with prostate cancer and undergoing prostatectomy as 
treatment of choice 
3.1.2 Index lesion visible on multiparametric MRI confirmed by targeted biopsies 
using KOELIS Trinity® 
3.1.3 Patient suitable for IV sedation or general anesthesia and TMA 
3.1.4 Free, informed, and written consent, dated and signed before the enrollment 
and before any exam required by the trial 
3.2 
Exclusion Criteria 
3.2.1 Past medical history of prostate surgery 
3.2.2 Past medical history of radiotherapy or pelvic trauma  
3.2.3 Past treatment for PCa (radiation, ablation, ADT, chemotherapy) 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
Microwave: Microwave radiation refers to the region of the electromagnetic 
spectrum with frequencies from 900 to 2450 MHz. Microwave can also be 
referred as “Ultra high radiofrequency” given the possible wavelength 
spectrum overlap. Water molecules have asymmetric electric charges. 
The alignment and the charges on the atoms are such that the hydrogen 
side has a positive charge, and the oxygen side has a negative charge. 
For a microwave oscillating at 9.2 x 108 Hz, the charge changes signs 
nearly 2 billion times per second. When an oscillating electric charge 
interacts with a water molecule, it causes the molecule to flip. Microwave 
is specially tuned to the frequency of water molecules to maximize this 
interaction. As a result of the microwave radiation hitting the water 
molecules, the water molecule flips back and forth 2–5 billion times per 
second depending on the frequency of the microwave energy. The 
vigorous movement of water molecules raises the temperature which is a 
measure of how fast molecules move. Therefore, electromagnetic 
microwaves heat matter by agitating water molecules in the surrounding 
tissue, producing friction, raise temperature, and induce cellular death via 
coagulation necrosis]. This is one major difference between microwave 
that treat simultaneously a whole volume and other energies relying on 
radial conduction of the energy from the antenna (cryotherapy, 
radiofrequency).  
 
 
We use MedWaves Avecure generator and associated microwave 
antenna, used for thermal microwave ablation. Under general anesthesia 
and ultrasound guidance, the prostate is visualized, and the optimal 
approach is determined. A thin (16-gauge) microwave antenna is then 
placed directly into the targeted area. When the antenna is attached to 
the microwave generator with a coaxial cable, an electromagnetic 
microwave is emitted from the noninsulated portion of the antenna. The 

________________________________________________________________________ 
15 
generator produces 10-60W of power at a frequency of 902-928 MHz. 
Intratissue temperatures can be measured with built-in temperature 
sensor [33].  
 
MRI/US fusion and OBT-Fusion®:   Targeted Microwave Ablation (TMA) is 
the specific wording when microwave is combined with an MRI/US fusion 
guidance system, the latter providing improved planning, guiding and 
visualization capabilities compared with conventional ultrasound systems. 
During the trial the KOELIS Trinity® system will be used. This 510k-
cleared medical device embeds four key technologies that are relevant for 
focal therapy using microwave: 
- 
3D Ultrasound using motorized ultrasound probes that allow to 
reconstruct the prostate in 3D in a few seconds with no probe 
movement. The ultrasound probe comes with guiding accessories 
(needle guides) to offer improved guidance of the diagnostic or 
therapeutic instrument in the prostate 
- 
Elastic MRI/US fusion allowing to precisely fuse a preoperative MRI 
containing relevant tumor information (location, size, aggressiveness) 
with intraoperative 3D Ultrasound to allow the physician to guide the 
needles directly inside the index tumor. This technology is necessary 
given that direct in-bore MRI guidance is cost and time consuming. 
- 
OBT-Fusion® is an image-based tracking technology that tracks and 
helps navigate the needle inside the prostate during the whole 
intervention. A patented algorithm then recognizes the needle location 
in a reference 3D ultrasound volume acquired at the beginning of the 
exam. The advantages are an increased accuracy due to the 
automatic patient and prostate movement during the exam, an 
absence of need of further sensors that are usually required to have 
such navigation capability, and an automatic recalibration throughout 
the exam instead of manual recalibration 
- 
2nd Look is a specific KOELIS technology that allows to recall the 
biopsy mapping information during a second intervention, which can 
typically be a focal treatment. The recalled information include the 
number of targeted and systematic cores, the location of MRI lesions 
that were biopsied, the histological features of each individual cores. 
The key advantage is the ability to further personalize the treatment 
plan according to each patient, rather than relying only on the MRI 
information. 
 
 
Dr. Andre Abreu who is an image-guided focal therapy expert will be 
delivering the TMA ablation for all the interventions[39]–[42].   
4.2 
Toxicities and Dosing Delays/Dose Modifications 
We will monitor for TMA related toxicities such as rectal injury, bladder injury, and 
perineal pain. Complications will be managed with best supportive care. Since 
previous literatures have not adapted similar study design (TMA and immediately 
resect), we do not have standard dosage of TMA needed to ablate planned area 
on the prostate. Therefore, we start from low output and ablation time and 
escalate them in accordance with corresponding histologically ablated area. 
 

________________________________________________________________________ 
16 
According to the manufacturer’s data based on other soft tissues, ablation 
coverages of short x long axis (cm) are estimated 1.5 x 2.5 for short-time 
(3min) ablation, 2.0 x 2.7 for medium-time (5min) ablation, and 2.5 x 3.0 
for long-time ablation.  
 
Based on the data, our TMA delivery strategy is planned as follows. 
 
 
Immediate resection phase 
 
1st patient  
Template #1 
Right lobe: Single Small (3min) Ablation 
Left lobe: Single Small (3min) Ablation 
2nd patient 
Template #2 
Right lobe: Single Medium (5min) Ablation 
Left lobe: Single Medium (5min) Ablation 
3rd patient 
Template #3 
Single lobe: Single Large (7.5min) Ablation 
4th patient 
Template #4 
Single lobe: Spatially-overlapped Double Medium-time (5min) Ablation 
5th patient 
Template #5 
Single lobe: Spatially-overlapped Double Large (7.5min) Ablation 
 
Delayed resection phase 
 
6-7th patient 
Template #1 
8-9th patient 
Template #2 
10-11th patient 
Template #3 
12-13th patient 
Template #4 
14-15th patient 
Template #5 
 
In order to avoid collateral damage and for safety, the TMA delivery protocol may 
be modified by the physician’s discretion but still in accordance with the 
manufacturer’s recommendation. 
 
 
4.3 
Concomitant Medications/Treatments 
NA. 

________________________________________________________________________ 
17 
4.4 
Other Modalities or Procedures 
 
4.4.1 Radical prostatectomy 
First 5 patients undergo RP immediately after TMA under the same anesthesia 
as their definitive treatment for PCa.  
Following 10 patients undergo RP one month after TMA under the general 
anesthesia as their definitive treatment for PCa This surgery is performed as 
standard of care. 
 
4.4.2 Duration of Therapy 
 
One session (one entire TMA procedure consisting of one to two ablations in 
accordance with TMA delivery protocol) only. 
4.5 
Removal of Patients from Protocol Therapy 
Patients can be taken off the study treatment and/or study at any time at their 
own request, or they may be withdrawn at the discretion of the investigator for 
safety, behavioral or administrative reasons. The reason(s) for discontinuation of 
treatment will be documented and may include: 
• 
Patient withdraws consent 
• 
Patient is unable to comply with protocol requirements 
• 
Patient experiences toxicity that makes continuation in the protocol unsafe 
• 
Treating physician determines continuation on the study would not be in the 
patient’s best interest 
Notify the Principal Investigator and document the reason for study removal and 
the date the patient was removed from treatment in the Case Report Form. The 
patient should be followed-up with per protocol. 
4.6 
Duration of Follow Up 
The study will begin at the time of informed consent and ends at 30 days (± 15 
days) visit following RP. No further follow-up is required as part of this study.  
4.7 
Patient Replacement 
Patients may be removed from the study at any time either via patient preference 
or failing to undergo either TMA or RP. If a patient is removed from the study, an 
additional patient may be enrolled. Patients who complete all procedures outlined 
in this protocol will be considered "fully evaluable", whereas those who fail to 
undergo any of the procedures (i.e. TMA or RP) will be considered “not fully 
evaluable”. We will report the numbers and percent of men considered “not 
evaluable”. If there are more than 1 or 2, we will try to figure out if there are any 
salient characteristics that distinguish “fully evaluable” from “not fully evaluable” 
patients. 
5.0 
STUDY PROCEDURES 
5.1 
Screening Phase and Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be 
done during initial clinical visit. It is acceptable to allow assessments performed 

________________________________________________________________________ 
18 
per standard clinical indications to be used for baseline values, but these again 
should be done within the screening window of 90 days or need to be repeated.  
 
The screening procedures include: 
 
Routine procedures done for patient’s medical care: 
5.1.1 Medical history 
Complete medical and surgical history. 
5.1.2 Demographics 
Age 
5.1.3 Review subject eligibility criteria 
5.1.4 Review previous and concomitant medications 
5.1.5 Physical exam and standard perioperative blood tests 
Vital signs (temperature, pulse, respirations, blood pressure), height, 
weight.  Bloods include full blood count, renal function and coagulation 
profile, tumor markers. 
5.2 
Randomization 
There will be no randomization in treatment allocation.  
5.3 
Treatment Procedures 
5.3.1 
Registered into study 
Once informed consent is obtained, patients will be registered into the study. We 
describe below all procedures that correspond to the treatment phase of our study: “TMA 
and RP phase” for the first 5 patients and “TMA phase” and “RP phase” for the following 
10 patients (refer to study schema).  
First 5 patients 
“TMA and RP PHASE” 
This phase of the study will be initiated within 30 days of registration.  
5.3.2 
Pre-TMA MRI (Only performed if not done within previous 6 months) 
• 
mp-MRI technique mp-MRI will be performed using a 3-T MR-750 MR-
scanner (General Electric, Waukesha, WI, USA) with a pelvic 16-channel 
phased-array body coil. Apparent diffusion co-efficiency (ADC)-map in 
diffusion weighted images (DWI) with the same orientation as transverse 
T2 weighted (T2-w) images. Dynamic contrast enhanced (DCE) image 
data will be post-processed with pharmacokinetic analysis software 
(iCAD, Nashua, New Hampshire). Lesions suspicious for clinically 
significant cancer in T2w, ADC-map, iCAD-DCE will be scored on a 
Prostate Imaging Reporting and Data System version-2.1 (PIRADS v.2.1) 

________________________________________________________________________ 
19 
scale from 1-5 by dedicated radiologists with expertise in prostate MRI 
[43]. T2w images will be manually segmented, the prostate outlined in 
each MRI plane and converted into a 3D object using specialized 
software. The final 3D prostate model will be imported into a 3D-design 
software (SolidWorks Corp., Concord, MA, USA) where it will be 
subtracted from a pre-generated rectangular mold to create an internal 
cavity that mirrors the patient’s prostate on MRI. The mold will be created 
by 3D printer (Dimension Elite 3D printer, Stratasys, Inc., Eden Prarie, 
MN, USA), and will be used for treatment planning. 
 
5.3.3 
TMA 
TMA preparation: The patients are instructed to self-apply rectal 2 
enemas: one the night before, one the morning of TMA; nothing per oral 
night prior (8hs) to TMA.  
Patient position and probe position: The patient is brought into the 
operating room and general anesthesia is obtained. Prophylactic 
antibiotic (Levaquin 500mg IV) is administered. The patient is placed in 
lithotomy position. The genitalia and perineal are prepped and draped in a 
sterile fashion. Digital rectal exam is performed. The 3D Side Fire 
endocavity TRUS probe (K3DEL00, Koelis, Meylan, France) is then 
inserted into the rectum.  
Ablation planning: The prostate is TRUS-scanned, the transverse and 
longitudinal images are acquired, the dimensions of the prostate are 
measured and the 3D volume of the prostate is acquired. The ultrasound 
(US) images are adjusted to provide optimal visualization of the prostate, 
rectal wall and surrounding tissues. The contours of the prostate are 
drawn to delineate the prostate contour, the urethra contour, the rectal 
wall contour. After fusion with the preoperative MRI, the ablation zones 
set by the manufacturer can be visualized in 3D as a simulation prior to 
the needle insertion.  
TMA delivery and monitoring: Under real-time TRUS guidance, a 
microwave antenna is transperineally inserted into the planned-ablation 
area. As much as possible, the needle will be placed at the center of the 
index tumor to maximize the treatment effect inside the lesion.  OBT-
Fusion® guidance ensures the proper location of the needle with respect 
to the targeted index lesion. Once the needle location is confirmed and 
the optimal treatment parameters are chosen, the microwave generator is 
configured accordingly, and the treatment can start. The ablation typically 
lasts for a few minutes. 
Post-treatment: After the procedure, the antenna and TRUS probe are 
withdrawn and the robotic RP as standard of care for the prostate cancer 
starts under same general anesthesia. Patients is sent to the recovery 
room for monitoring. After completely recovery from the anesthesia the 
patient stays hospital overnight or is discharged home with the urethral 
Foley in place. Prescriptions are provided for: bladder antispasmodic, 
anti-inflammatory, and antibiotics.  

________________________________________________________________________ 
20 
5.3.4 Pathologic Evaluation  
Following prostatectomy, the prostates will primarily be evaluated using 
standard-of-care diagnostic methods, and secondarily be assessed in 
accordance with the thermal treatment parameters. The intact prostate 
specimens should be received in pathology within two up to six hours of 
prostatectomy. Standard gross examination of prostate specimens will be 
done including measurement, appropriate inking for margins and serial 
transverse sectioning from the bladder neck across the prostate to the 
penile urethral margin. Digitally photographing of these sections will be 
done. TTC viability staining will be performed not less than 2 hours after 
TMA and 4 up to 6 hours after completion of prostatectomy. Macroscopic 
evaluation of the TTC stained sections will be performed where viable 
tissues would exhibit maroon color change, while ablated non-viable 
tissues should show absence of color change. Routine tissue processing 
and H&E staining will be performed. H&E stained whole mount sections 
of the prostatectomy specimens will be evaluated on microscopy. If 
indicated, IHC staining will be done.  
 
Following 10 patients 
“TMA PHASE” and 1mo delayed “RP PHASE” 
5.3.5 
Pre-TMA MRI (Only performed if not done within previous 6 months) 
5.3.6 
mp-MRI technique: The same as the first 5 patients.  
5.3.7 
 TMA 
TMA preparation:  
Patient position and probe position:  
Ablation planning:  
TMA delivery and monitoring: The same as the first 5 patients.   
Post-treatment: After the procedure, the antenna and TRUS probe are 
withdrawn. Patients is sent to the recovery room for monitoring. After 
completely recovery from the anesthesia the patient stays hospital 
overnight or is discharged home with the urethral Foley in place. 
Prescriptions are provided for: bladder antispasmodic, anti-inflammatory, 
and antibiotics. 
5.3.8 
RP 
30 days (±15days) after TMA, the robotic RP as standard of care for the 
prostate cancer starts under same general anesthesia. Just prior to RP, 
MRI/TRUS fusion transperineal biopsy will be performed under the same 
anesthesia of RP. Then the RP will be immediately carried out as per 
SOC. After RP, the patient is sent to the recovery room for monitoring. 
After completely recovery from the anesthesia the patient stays hospital 
overnight or is discharged home with the urethral Foley in place. 
Prescriptions are provided for: bladder antispasmodic, anti-inflammatory, 
and antibiotics.  
 

________________________________________________________________________ 
21 
5.4 
Follow-up Procedures 
First 5 patients 
“Follow-up PHASE” 
5.4.1 
The patient returns to clinic in 10 (±5) days after TMA and immediate RP 
for removal of urethral Foley and formal voiding trial. An AE assessment 
is performed at this time. 
“Completion PHASE” 
 
5.4.2 
Patients will do a follow-up visit 30 (±10) days after TMA and immediate 
RP per standard of care. Adverse effects will be assessed during this 
visit. Tests for perineal discomfort, PSA, IPSS, IIEF-5, EPIC-26, 
uroflowmetry and patient satisfaction questionnaire are assessed. 
5.4.3 
Adverse event assessment 
 
Adverse events will be assessed. See section 7 for Adverse Event 
monitoring and reporting 

________________________________________________________________________ 
22 
Following 10 patients 
“Follow-up PHASE 1” 
After TMA, the patient returns to clinic in 10 (±5) days. An AE assessment is performed 
at this time. 
“Follow-up PHASE 2” 
5.4.4 
After TMA, the patient returns to clinic in 30 (±10) days for IPSS, IIEF-5, EPIC26, 
uroflowmetry, PSA, MRI and AE evaluation. These will be performed prior to RP. 
“Follow-up PHASE 3” 
5.4.5 
After RP, the patient returns to clinic in 10 (±5) days for removal of urethral Foley. An AE 
assessment is performed at this time. 
 
“Completion PHASE” 
 
5.4.6 
Patients will do a follow-up visit 30 (±15) days after RP per standard of care. Adverse 
effects will be assessed during this visit. Tests for perineal discomfort, PSA IPSS, IIEF-5, 
EPIC-26, uroflowmetry, and patient satisfaction questionnaire are assessed. 
5.4.7 
Adverse event assessment 
Baseline adverse events will be assessed. See section 7 for Adverse Event monitoring 
and reporting 

________________________________________________________________________ 
23 
 
5.5 
Study Calendar 
First 5 patients 
 
 
Screening 
visit 
Treatment date 
Follow-up Phase 
Completion 
phase 
 
 
Day 0  
Day 10 (±5) 
Day 30 day 
(±10) 
 
 
OR 
pre-TMA 
TMA 
OR 
post-TMA 
 
 
Medical history 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medication review 
X 
 
 
 
 
Adverse Event 
assessment 
X 
X 
 
X 
X 
X 
Physical Exam 
X 
 
 
X 
X 
Vital Signs 
(temperature, 
pulse, respiration, 
BP, (height and 
weight -only on 
screening) 
X 
 
 
X 
X 
Hematology, full 
blood count, renal 
function and 
coags 
X 
 
 
 
 
PSA 
measurement 
X 
 
 
 
X 
Patient eligibility 
review, enrollment  
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
MRI 
X 
 
 
 
 
Uroflowmetry 
X 
 
 
 
X 
Catheter removal 
 
 
 
X 
 
IPSS, IIEF-5 and 
EPIC-26   
questionnaires 
X 
 
 
 
X 
Urine analysis and 
culture 
X 
 
 
 
 
Radical 
prostatectomy 
 
 
 
X 
 
 
TMA delivery 
 
 
X 
 
 
 
Pathology 
 
 
 
X1 
 
 
1: Pathologic evaluation including TTC staining is performed immediately after RP. 
 
 
 

________________________________________________________________________ 
24 
Following 10 patients 
 
 
Screening 
visit 
Treatment date 
Follow-
up 
Phase1 
Follow-
up 
Phase2 
RP 
date 
Follow-
up 
Phase3 
Completion 
phase 
 
 
Day 0  
Day 10 
(±5) 
Day 30 
(±5)2 
Day 30 
(±5) 
Day 40 
(±5) 
60 days (±10 
days) 
 
 
OR 
pre-
TMA 
T
M
A 
OR 
post-
TMA 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medication 
review 
X 
 
 
 
 
 
Adverse Event 
assessment 
X 
X 
 
X 
X 
X 
 
X 
X 
Physical Exam 
X 
X 
X 
 
X 
X 
Vital Signs 
(temperature, 
pulse, 
respiration, BP, 
(height and 
weight -only on 
screening) 
X 
X 
X 
 
X 
X 
Hematology, full 
blood count, 
renal function 
and coags 
X 
 
 
 
 
 
PSA 
measurement 
X 
 
X 
 
 
X 
Patient eligibility 
review, 
enrollment  
X 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
MRI 
X 
 
 
X 
 
 
 
Uroflowmetry 
X 
 
X 
 
 
X 
Catheter 
removal 
 
X 
 
 
X 
 
IPSS, 
IIEF-5 
and EPIC-26   
questionnaires 
X 
 
 
X 
 
 
X 
Urine analysis 
and culture 
X 
 
 
 
 
 
 
Intra-operative 
prostate biopsy 
 
 
 
 
 
X 
 
 
Radical 
prostatectomy 
 
 
 
 
 
X 
 
 
TMA delivery 
 
X 
 
 
 
 
 
 
Pathology 
 
 
 
 
 
X3 
 
 

________________________________________________________________________ 
25 
2: The date of Follow-up Phase2 is scheduled 1-5 days before RP date. 
3: Pathologic evaluation without TTC staining is performed after RP. 
6.0 
MEASUREMENT OF EFFECT 
The main effect we will measure to achieve our primary objective is the treatment 
effect (proportion of dead tissue - benign and cancerous) inside the TMA-treated 
zone on the prostatectomy specimen. The excised prostate will be sliced at 4 mm 
intervals. Each slice will be embedded, and a pathologist will examine slides 
corresponding to each slice. The pathologist will be blinded to MR and TRUS 
imaging results. TTC and/or H&E staining are performed to determine thermal 
ablation zone size/location/relationship to urethra seminal vesicles capsule and 
other structures. 
7.0 
ADVERSE EVENTS 
7.1 
 Experimental Therapy 
7.1.1 One-month delayed resection 
Prostate cancer is usually a slow-growing cancer even in the setting of high-risk 
disease. Therefore, delaying RP doesn’t impact on earlier, medium- or long-term 
oncologic and functional outcomes [44-46]. On a period of one month from TMA 
to RALP, the functional outcomes should not be affected by the TMA. In fact, the 
one-month delay from TMA to RP is long enough to allow for decreasing peri-
prostatic edema, however short enough to avoid tissue fibrosis, retraction and 
adhesion that would happen with prolonged delay from TMA. The functional 
outcomes should be dictated/related to RALP, patients’ and cancer 
characteristics such as nerve sparing RALP technic, urethral length, patients 
age, etc. The TMA will not be performed with a curative intent, in fact, it will be 
performed conservatively, sparing the boundaries of the prostate to avoid 
damage to the neurovascular bundles and the rectum. Furthermore, there will be 
a dose-escalation approach, where the TMA will be performed from small to 
larger ablation areas allowing for precise evaluation of the ablated area in each 
planned ablation template. 
7.1.2 Two-separated procedures 
The risks of the operations are according to each operation individually. Focal 
therapy for prostate cancer (HIFU and Cryoablation) is routinely performed by 
USC urologists. In fact, we have one of the largest experiences with ablation 
therapy for PCa in the US [42,47]. These procedures are safe with low risk of 
perioperative complications and lower risks of severe adverse events. In our 
initial series of 100 consecutive men who underwent HIFU focal therapy for PCa, 
approximately 13% of the patient experienced adverse events being the most 
common urinary retention, requiring prolonged catheterization, and urinary 
infection, requiring antibiotics [39]. No patient underwent additional intervention 
due to complications/adverse events. Additionally, there were no anesthesia-
related complications. It is important to note that these patients were treated with 
a curative intent with large areas of ablation often extending towards to the 
urethra. Recent trials investigating TMA also demonstrated the feasibility and 
safety [26-28]. For the current PRAMA study, the TMA approach will be more 
conservative because the intent isn’t curative, therefore the urethra and 
surrounding organs will be preserved. As such, we expect lower chances of side 
effects. The anesthesia risks related to RALP is similar to the approximately 600 

________________________________________________________________________ 
26 
RALPs annually performed by USC urology. The anesthesia risk shouldn’t be 
affected by the TMA prior to RALP. 
 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of 
every clinical trial, are done to ensure the safety of Subjects enrolled in the 
studies. Adverse events are reported in a routine manner at scheduled 
times during a trial. For this study, the AEs will be monitored and recorded 
at the day of surgery and each postop visit, per study calendar. 
Additionally, certain adverse events must be reported in an expedited 
manner to allow for optimal monitoring of patient safety and care. 
7.3 
Definition 
7.3.1 
Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient 
receiving study treatment and which does not necessarily have a causal 
relationship with this treatment. Based on pilot data, there are no adverse 
events associated with performing TMA in patients who are candidates 
for RP. The AEs of interest for this study include: 
Acute urinary retention: any episode of urinary retention following surgery, 
needed catheterization.  
Hematuria: Any gross blood/clot in the urine, needed bladder irrigation. 
 
7.3.2 
Severity of Adverse Events 
All adverse events will be graded according to the Clavien Dindo 
Classification (CDC) in the post-operative prostatectomy setting (outlined 
below).  
The Clavien Dindo classification is available at 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1360123/ 
Adverse events are monitored and recorded in accordance with Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 as well, although 
the safety of the protocol is evaluated based on CDC.CTCAE v5.0 is 
available at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50 
Clavien Dindo Classification (CDC) 
Grade I Any deviation from the normal postoperative course without the need for pharmacological 
treatment or surgical, endoscopic and radiological interventions 
Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics 
and electrolytes and physiotherapy. This grade also includes wound infections opened at 
the bedside. 
Grade II Requiring pharmacological treatment with drugs other than such allowed for grade I 

________________________________________________________________________ 
27 
complications. Blood transfusionsand total parenteral nutritionare also included. 
Grade III Requiring surgical, endoscopic or radiological intervention 
IIIa 
Intervention not under general anesthesia 
IIIb 
Intervention under general anesthesia 
Grade IV Life-threatening complication (including CNS complications)* requiring IC/ICU-
management 
IVa 
Single organ dysfunction (including dialysis) 
IVb 
Multi organ dysfunction 
Grade V Death of a patient 
7.3.3 
Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any 
untoward medical occurrence that: 
1. 
Results in death 
2. 
Life-threatening event 
3. 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
4. 
Results in persistent or significant disability or incapacity or 
substantial disruption of the ability to conduct normal life 
functions 
 
7.3.4 
Is life-threatening  
Only SAEs that are judged by the Principal Investigator to be related or 
possibly related to TMA and not part of the expected post-operative 
course will be assessed and reported.  
• The patient was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death 
if it were more severe. 

________________________________________________________________________ 
28 
• Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly/birth defect 
• Is an important medical event 
• Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event 
may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
7.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the Clavien Dindo Classification 
(CDC).  
 
Step 2: Grade the adverse event using the CDC. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
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 unlikely related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of 
protocol treatment. Any event that occurs more than 30 days after the last dose 
of treatment and is attributed (possibly, probably, or definitely) to the agent(s) 
must also be reported accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity 
of the event is not listed in the current known adverse events including rectal 
injury, urethral injury, acute urinary retention, perineal pain and uncontrollable 
hematuria. 
7.5 
Reporting Requirements for Adverse Events 
 
Expedited Reporting 
• 
The Principal Investigator must be notified within 24 hours of learning 
of any serious adverse events, that were possible related to the 
research procedures..  

________________________________________________________________________ 
29 
• 
The Institutional IRB will be notified in accordance with the 
institutional policy about any unanticipated problems involving risk to 
subjects or others (UPR). 
 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other 
problems), which in the opinion of the Principal Investigator was 
unanticipated, involved risk to subjects or others, and was 
possibly related to the research procedures. 
2. Any serious accidental or unintentional change to the IRB-
approved protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, 
updated sponsor safety report), interim result or other finding that 
indicates an unexpected change to the risk/benefit ratio for the 
research. 
5. Any breach in confidentiality that may involve risk to the subject or 
others. 
6. Any complaint of a subject that indicates an unanticipated risk or 
that cannot be resolved by the Principal Investigator. 
• 
The USC NCCC Data and Safety Monitoring Committee (DSMC) 
must be notified within 24 hours of submission of such reportable 
event to the  IRB. The patient ID and the study number as well as 
identifier of the SAE report should be submitted to the DSMC 
Coordinator via email or Fax to the attention of the DSMC 
Coordinator at 323-865-0089. 
 
Routine Reporting 
• 
All other adverse events- such as those that are expected, or are 
unlikely or definitely not related to the study participation- are to be 
reported annually as part of regular data submission.  For studies 
requiring USC DSMC review, this report should also be forwarded to 
the DSMC Coordinator.  If USC holds the IND, a list of all toxicities 
will be included in the IND annual report.   
7.6 
Unblinding Procedures For Blinded and Randomized trials 
• 
NA 
 
7.7 
Monitoring Rules for Safety   
All other adverse events- such as those that are expected or are unlikely or 
definitely not related to the study participation- are to be reported as part of 
regular data submission. 
 

________________________________________________________________________ 
30 
We will pause study enrollment after 10 patients if 2 or more patients do not 
progress to RP and perform a thorough assessment as to ongoing safety of the 
study.  
 
If a severe adverse event related to TMA occurs during TMA procedure or by 
follow-up phase (Day 10 ± 5) for immediate resection phase or by follow-up 
phase 3 (Day 40 ± 5) for delayed resection phase, we assess, discuss, and 
tabulate the severe adverse event. 
 
To ensure safety, the next patient’s TMA will be scheduled at least after follow-up 
phase of the previous patient for immediate resection phase. For delayed 
resection phase, the next patients for the different TMA template will be 
scheduled at least after follow-up phase 3 of the previous patients. 
 
In addition, for the delayed resection phase, in the case that two in two patient 
who underwent the same TMA template experienced severe adverse events 
related to TMA, we stop to proceed the next TMA template. 
 
We set 30% as clinically acceptable severe adverse events (defined as CDC ≥3) 
rate (i.e. less than 4 in 10 delayed resection cases). 
8.0 
DEVICE INFORMATION 
All the investigational devices required in the PRAMA protocol to perform the TMA procedure 
are 510(k)-cleared and used in accordance with their respective indications for use, as 
described below: 
• 
Based on the 510(k) of AveCureTM Ablation System (reference: K143203): 
“The MedWaves AveCureTM Ablation System is intended for use in percutaneous, 
laparoscopic, and intraoperative coagulation-ablation of soft tissue. The MedWaves 
AveCureTM Ablation System  is not intended for use in cardiac procedures.” 
• 
Based on the 510(k) of TRINITY / 3D PROSTATE SUITE (reference: K170521):  
“TRINITY and its embedded 3D PROSTATE SUITE software are intended to be used by 
clinicians and their assistants, qualified to perform ultrasound diagnosis and ultrasound-
guided procedures, in public of private hospitals. TRINITY is indicated to: 
o Generate ultrasound images for structural analysis and fluid flow analysis for 
 
Urology,  
 
Gynecology,  
 
Vascular,  
 
Abdominal,  
 
Small organs,  
 
Soft tissues and  
 
Musculoskeletal exams 

________________________________________________________________________ 
31 
TRINITY is not indicated for ophthalmic and cranial ultrasonography.” 
 
To summarize, the TMA procedure will be performed on soft tissue (prostate). The ablation will 
be achieved thanks to MedWaves AveCureTM Ablation System under ultrasound-guidance 
using TRINITY. Besides, the risks associated with this procedure are known, controlled and 
well-described, as previously outlined, qualifying the procedure as a non-significant risk 
procedure.  
 
 
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
  
 
9.1. 
Correlation of histology with MRI 
Following prostatectomy, the prostates will primarily be evaluated using standard-of-care 
diagnostic methods, and secondarily be assessed in accordance with the thermal treatment 
parameters. The intact prostate specimens should be received in pathology within two up to six 
hours of prostatectomy. Standard gross examination of prostate specimens will be done 
including measurement, appropriate inking for margins and serial transverse sectioning from the 
bladder neck across the prostate to the penile urethral margin. Digitally photographing of these 
sections will be done. TTC viability staining will be performed not less than 2 hours after TMA 
and 4 up to 6 hours after completion of prostatectomy. Macroscopic evaluation of the TTC 
stained sections will be performed where viable tissues would exhibit maroon color change, 
while ablated non-viable tissues should show absence of color change. Routine tissue 
processing and H&E staining will be performed. H&E stained whole mount sections of the 
prostatectomy specimens will be evaluated on microscopy. If indicated, IHC staining will be 
done.  
 
 
10.0 
STATISTICAL CONSIDERATIONS  
 
All patients who sign the consent and are registered will be accounted for. However only 
those patients who undergo TMA and who undergo the radical prostatectomy will be 
included in the primary analyses; these will be the fully evaluable patients. Those who 
fail to complete the protocol as planned will be summarized; reasons for failure to 
complete will be examined.  
10.1 
Summary of Design 
This is a feasibility study to evaluate whether TMA is promising as a stand-alone 
local treatment for men with localized prostate cancer, thereby eliminating the 
need for prostatectomy or standard radiation as the primary treatment. For 
practical considerations, the total number of study participants is limited to 15 
patients by 1) cost and 2) feasibility (could not do many more during the funding 

________________________________________________________________________ 
32 
period). The number of patients included may be extended considering the need 
to evaluate different treatment parameters (still according to manufacturer data). 
10.2 
Justification of Trial Design.  
• 
The decision to evaluate at 5 patients in immediate resection phase would 
provide intraoperative safety and feasibility, and evaluation of the ablated area on 
the radical prostatectomy specimen assessed by TCC stanning according to 
TMA delivery protocols. The decision to evaluate at 10 patients in delayed 
resection phase would provide intraoperative safety and feasibility, in addition to 
estimate of the short-term safety after TMA, evaluation for functional status 
(urinary symptoms, potency, incontinence), PSA response, MRI evaluation, 
prostate biopsy evaluation, safety and feasibility of salvage prostatectomy after 
TMA, and evaluate tissue viability on HE stanning. Additionally, The post-TMA 
MRI and prostate biopsy performed just prior to the delayed radical 
prostatectomy will be used to predict/evaluate the actual prostatectomy findings. 
  
 
10.3 
Primary Objective Statistical Considerations 
To determine the feasibility of transperineal targeted microwave ablation of an 
MRI-identified index prostate tumor in patients undergoing radical prostatectomy, 
we will evaluate the viable tissue remaining after TMA using histologic 
examination of excised prostate specimen.  
 
 
 
10.4 
Secondary Objective Statistical Considerations 
The intra-operative safety of the targeted microwave ablation, the number of 
microwave ablations needed to ablate one mpMRI-visible lesion, the ease of use 
of the operative procedure and the feasibility of the immediate or 1 mo delayed 
radical prostatectomy after the targeted microwave ablation will also be 
evaluated. 
 
10.5 
Descriptive Objective Statistical Considerations 
NA   
10.6 
Sample Size and Patient Accrual 
Due to the nature of exploratory and feasibility study design, the sample size of 
15 subjects was determined by practical considerations, including cost and 
feasibility (could not do many more during the funding period). 
Through the immediate resection phase, 5 practical TMA templates and 
their ablation areas are evaluated. With following the delayed resection 
phase, the short-term safety and feasibility of TMA templates are 
evaluated. 
The number of patients included may be extended considering the need to 
evaluate different treatment parameters (still according to manufacturer 
data). 

________________________________________________________________________ 
33 
 
10.7 
Data Analyses Plans 
All patients who sign the consent form will be registered and entered the 
database. For each patient, we will list whether he received the assigned protocol 
(and if not, the reasons), the outcome of the procedures, compliance with the 
protocol (and reasons for failure to comply), adverse events with any of the 
procedures, MRI results, and targeted biopsy results.  
 
• 
The data from the immediate resection phase and delayed resection phase will 
be separately evaluated. The observed ablated area in immediate resected 
prostatectomy specimen based on TTC staining will be compared with the 
predicted ablation area according to the template. The tissue viability will be 
evaluated by HE staining on delayed resection prostatectomy specimen. 
• 
The comparison of the difference between the treatment effect dimensions 
measured histologically on the prostatectomy specimen resected after TMA and 
the predictive ablation charts provided by the manufacturer will be performed. For 
this analysis, the data from immediate resection phase and delayed resection 
phase are separately evaluated.  
• 
The comparison between the treatment effect dimensions measured 
histologically on the prostatectomy specimen resected one month after TMA, 
compared to post TMA dimensions measured on the pre-RP mpMRI. 
• 
To evaluate the intra/post-operative safety of TMA, we defined 30% as clinically 
acceptable severe adverse events (defined as CDC ≥3) rate. If the severe 
adverse events occur less than 30% (equivalent to less than 4 cases in 10 
cases) for the delayed ablation phase, the feasibility of TMA is proved.  
 
Immediate resection phase 
If a severe adverse event related to TMA occurs during TMA procedure or by 
follow-up phase (Day 10 ± 5), we assess, discuss, and tabulate the severe 
adverse event. For this evaluation, TMA-related adverse events include rectal 
injury, and urethral injury. 
 
Delayed resection phase 
If a severe adverse event related to TMA occurs during TMA procedure or by 
follow-up phase 3 (Day 40 ± 5), we assess, discuss, and tabulate the severe 
adverse event. In the case that two in two patient who underwent the same TMA 
template experienced severe adverse events related to TMA, we stop to proceed 
the next TMA template. For this evaluation, TMA-related adverse events include 
rectal injury, urethral injury, acute urinary retention, and uncontrollable hematuria. 
 
Adverse events are also recorded in accordance with Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0.  
 
• 
TMA procedure duration: probe-in / probe-out time, ablation time will be 
recorded. 
• 
The ablation location in the prostate as seen in the KOELIS 3D map and the 
ablation location observed histologically on the prostatectomy specimen will be 
recorded. 

________________________________________________________________________ 
34 
• 
The change in functional outcomes between baseline and each follow-up visit, 
using IPSS, IIEF-5, EPIC-26 and uroflowmetry is recorded. For delayed resection 
phase, functional outcomes between baseline and follow-up phase 2 will be 
estimated as average change. 
• 
The post-TMA MRI and prostate biopsy performed just prior to the delayed 
radical prostatectomy will be reported.  
10.8 
Reporting and Exclusions   
 
Evaluation of toxicity.   
We will monitor for TMA related toxicities such as rectal injury, urethral 
injury, acute urinary retention, perineal pain and uncontrollable hematuria. 
Complications will be managed as per standard of care in accordance with 
CDC. 
 
Evaluation of response.  NA.  
 
11.0 
STUDY MANAGEMENT       
11.1 Conflict of Interest 
All investigators will follow the University conflict of interest policy. Any USC 
investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, 
etc.) must complete a “Statement of Outside Interests Related to Research” 
Form. The application is reviewed and approved by the Conflict of Interest 
Review Committee (CIRC) USC conflict of interest policy is available at  
http://ooc.usc.edu/conflict-interest-research 
 
11.2 
Institutional Review Board (IRB) Approval and Consent Process 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB should approve the 
consent form and protocol and all study related documents used in the study 
(e.g. QOL questionnaire, pill diary, brochure, advertisement etc). 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing a dated 
IRB-approved consent form. 
 

________________________________________________________________________ 
35 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person 
authorized to obtain the informed consent  
 
11.3    Required Documentation (for multi-site studies) 
 
 Not required  
11.4  Registration Procedures 
 USC Registration:  
 
The Research Coordinator must complete the protocol eligibility form to ensure   
that the patient is eligible. The PI will review the patient eligibility (with assistance 
from the Research Coordinator- who will assemble the required source 
documents, and do an initial review) prior to registering the patient on study. 
 
 The Research Coordinator or data manager will then register the patient into the 
Cancer Center database, Café, by accessing the Registration forms. Likewise, 
after the patient has completed the study, the Off Study forms in cafe will need to 
be completed, for Off Treatment and Off Study. 
 
11.6   RECORDS AND DATA SUBMISSION 
A. Confidentiality of Records 
The original data collection forms will be kept in secure file cabinets, for USC 
patients forms will be kept in the Clinical Investigations Support Office (CISO).  
 
B.  Patient Consent Form   
At the time of registration, signed and dated copies of the patient Informed 
Consent with the Human Rights and the HIPAA authorization must be given to 
the patient. Institutional policy regarding distribution and location of original 
consent documents should be followed.  When a study is opened at two or more 
institutions, a copy of the signed consent and HIPAA should be sent to USC 
CISO QA team as soon as possible, and not later than within 5 business days of 
obtaining consent.  For patients consented at USC/LAC, institutional policy 
should be followed: a copy of ICF and HIPAA should be uploaded through   True 
to USC CRO and to CISO QA Team. The original will be kept in the patient 
research chart maintained by the study assigned Data Manager. 
 
C.   Registration Eligibility Worksheet   
At the time of registration, the completed Eligibility Worksheet will be submitted to 
the QA Monitor at CISO for review of eligibility compliance. 
 
D. Data Collection Forms and Submission Schedule 
If a treatment trial, protocol data will be entered into eCRFs in Café. 
Within two weeks of registration, the data manager will complete the initial set of 
On Study forms and baseline Toxicities 
Within two weeks of completion of each course of treatment, the data manager 
must complete the Course Assessment, Toxicities, and if appropriate Response 
data. 

________________________________________________________________________ 
36 
• After Off Treatment, within two weeks of each follow up, complete the 
Follow Up forms. 
11.7  Data Management and Monitoring/Auditing            
11.7.1  Active Monitoring Program Details 
a. 
Adherence to Protocol/Per Patient: It is the responsibility of the 
Principal Investigator (PI) to ensure that patient recruitment and enrollment, 
treatment, follow-up for toxicities and response, and documentation and reporting 
are all performed as specified in the protocol.  
b. 
Day-to-Day Monitoring – Eligibility:  The Study Coordinator will assist 
the investigator in reviewing eligibility and  will assemble the required source 
documents, and do a final review by completing an Eligibility Registration 
Worksheet.The Eligibility Registration Worksheet with a copy of Informed 
Consent and supporting source documents will be submitted to CISO QA via 
email or Fax for verification prior to registering the patient on study. 
c. 
Day-to-Day Monitoring – Informed Consent: Prior to registering the 
patient on study, the Study Coordinator will review the informed consent, to 
ensure that the patient has signed and dated the most current IRB-approved 
form, and that the form has been signed and dated by the person obtaining the 
consent as well as appropriate witnesses. A copy of the ICF will also be provided 
to CISO QA for review. CISO SOP 3.3 will be followed.  
d. 
Day-to-Day Monitoring – Treatment: The PI and co-investigators are 
responsible for ensuring that treatment is given per protocol. The Study 
Coordinator will review the treatment orders with the treating investigator. The 
treating investigator will review the status of each patient on-study, with the Study 
Coordinator and the treating physician, on an on-going basis.   
e. 
Data Management – Patient Charts: At USC, all written source 
documents not associated with the study research are maintained in the patient 
chart, which is stored in the Department of Medical Records at the appropriate 
hospital. At the Norris Hospital, the official medical record is the Electronic 
Patient File (EPF). Radiographical images are stored in the Department of 
Radiology and in an electronic system called Synapse. These are the permanent, 
official documents for each patient on-study. A copy of the signed informed 
consent, physician’s notes, orders, test results and pathology notes are 
maintained in the patients’ hospital charts. It is the responsibility of the research 
staff to ensure that the patient chart contains the required documents and work 
closely with treating investigators to ensure all protocol-related assessments are 
carefully documented. 
f. 
Data Management – Research Charts: To facilitate adherence to the 
protocol schedule and data management, research charts are created to collect 
copies of the relevant notes, orders and results, that are in the Patient Chart. In 
Addition, all source documents related to the research, such as original informed 
consent forms, HIPAA Forms, AE assessment worksheets, disease response 
worksheets and NTFs are maintained in the Research Charts. Protocol 
calendars, worksheets, and checklists, are also kept in the research chart. These 
are maintained in the Clinical Investigation Support Office until the study is 
completed and the results are published and no further need is anticipated. 

________________________________________________________________________ 
37 
These are then stored off-site. It is the responsibility of the Data Manager to 
ensure that the research chart contains all the required documents. 
g. 
Data Management – Case Report Forms: It is the responsibility of the 
Data Manager to complete the required case report forms. The case report forms 
are developed for the trial and these are used to finalize the data entry screens in 
the Cancer Center clinical trials database. It is the responsibility of the PI to 
review the Off-Study Summary form which summarizes pertinent toxicity, 
response and adherence information, once the patient has completed treatment. 
11.7.2 Quality Assurance Monitoring Committee (QAMC) Oversight 
 
The Quality Assurance and Monitoring Committee (QAMC) of the NCCC has the 
responsibility for study auditing and monitoring for protocol compliance, data 
accuracy, performance of audits and monitoring of accrual. QAMC procedures 
are detailed in the NCCC Data Safety and Monitoring Plan available on CISO 
Website. 
11.7.2.1 QAMC Annual Patient Audits 
The QAMC is responsible for conducting audits and providing the initial review of 
the audits.  The trial is audited by the QAMC once a year. Faculty and staff at the 
Cancer Center involved in clinical research – but not directly involved in the 
research under evaluation – are asked to serve as auditors. Twenty percent of 
patients accrued during the past 12 months – and a minimum of 2 patients – are 
selected at random; however, additional patients may be selected for audit if 
there is some indication that there might have been a problem or unusual 
circumstance (possibly related to compliance, toxicity, response or some 
indication of an irregularity). The audit involves a review of the research chart, 
hospital medical record (i.e., source documentation) and evaluates the following: 
documentation of eligibility (including failure to obtain appropriate informed 
consent) and baseline status of the patient; documentation of adherence to 
protocol-specified treatment and follow-up; evaluation of toxicity; and evaluation 
of response or other outcome. In addition, for Institutional, Investigator Initiated 
Trials, Data in the CAFÉ database are compared to the information in the 
medical record.   
11.7.2.2   
QAMC Annual Protocol Review 
All open trials are reviewed at least once a year by the QAMC (or more often if 
stipulated by the CIC). This annual review includes the following: evaluation of 
the current accrual relative to the planned total accrual; examination of gender 
and minority accrual; examination of all reported violations; review of past audits 
and correspondence with the PI; review of results of current audit (by an outside 
agency or by the NCCC QAMC); review of previous correspondence between the 
PI and the QAMC/DSMC. The QAMC review process is detailed in USC NCCC 
DSM Plan available on the CISO website. 
11.7.3 Data and Safety Monitoring Committee (DSMC) Oversight 
 The Data and Safety Monitoring Committee (DSMC) is an independent body responsible 
for the safety of study subjects through the review of new protocols to ensure an 
adequate adverse event assessment/reporting plan, study stopping rules and through the 
real-time and periodic monitoring of severe adverse events (SAEs) or those AEs that 

________________________________________________________________________ 
38 
require expedited reporting. The DSMC performs quarterly and annual safety reviews as 
well as interim efficacy/futility analyses on institutional trials. DSMC procedures are 
detailed in USC NCCC DSM Plan available on the CISO website. 
11.8  
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.  
11.8.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the 
protocol to eliminate an immediate hazard(s) to trial subjects without prior 
IRB approval.  
 
For any such emergency modification implemented, an IRB modification 
form must be completed within five (5) business days of making the 
change.  
11.8.2    Non-Emergency departures from protocol  
A protocol deviation is any variance from an IRB approved protocol.  
If the deviation meets all of the following criteria, it is considered a minor 
protocol deviation that:  
• 
Is generally noted or recognized only after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research 
plan or the value of the data collected  
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
If the deviation meets any of the following criteria, it is considered a 
protocol violation: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the 
investigator(s). 
• 
Demonstrates serious noncompliance with federal regulations, State 
laws, or University policies. 
 
Protocol Deviations: personnel will report to any sponsor or data and 
safety monitoring committee in accordance with their policies.  
 
Protocol Violations: All protocol violations will be entered in the clinical 
trial database by the Research Coordinator. In addition, Research 
Coordinator and Investigator should report all protocol violations within 
one (1) week of the knowledge of the event using iStar. 

________________________________________________________________________ 
39 
11.8.3    Amendments to the Protocol    
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator. It should also be 
noted that when an amendment to the protocol substantially alters the 
study design or the potential risk to the patient, a revised consent form 
might be required.  
 
The written amendment, and if required the amended consent form, must 
be sent to the IRB as well as to all the sponsoring agencies (FDA, NCI, 
etc.) for review and for approval prior to implementation. It is the 
responsibility of the study PI to ensure that the appropriate agencies have 
been informed of the proposed amendments and that these have been 
reviewed and approved.   
11.9      Record Retention   
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator 
must retain all study documentation pertaining to the conduct of a clinical trial. In 
the case of a study with a drug seeking regulatory approval and marketing, these 
documents shall be retained for at least two years after the last approval of 
marketing application in an International Conference on Harmonization (ICH) 
region. In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 
11.10    Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
Moreover, the Principal Investigator will be responsible for assuring that all the 
required data will be collected and entered onto the Case Report Forms. 
Periodically, monitoring visits will be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of 
data. At the completion of the study, all case report forms will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the accuracy 
of the data. 
 
12.0 
REFERENCES 

________________________________________________________________________ 
40 
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Cooperberg MR and Carroll PR: Trends in Management for Patients With Localized 
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13.0 
APPENDICES 
Ablation Delivery Strategy