Clinical trial NCT04495894
Conditions: Non-small Cell Lung Cancer Renal Cell Carcinoma
Keywords: Surgery
Sponsor: Emory University
Start date: 2020-08-24; Completion date: 2024-02-01
Enrollment: 68 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a pilot study of biomarker evaluation and safety of pre-incisional ketorolac for patients undergoing surgical resection for non-small cell lung cancer and renal cell carcinoma. There is significant promise in the use of preoperative ketorolac to decrease the inflammatory response after surgical resection of tumors, thereby potentially reducing the risk of distant metastatic tumor spread and improving survival. This research will advance scientific knowledge by studying the safety of a preoperative dose of ketorolac prior to major surgical resection, which needs to be assessed prior to proceeding with a larger phase II study designed to evaluate traditional efficacy endpoints such as recurrence and overall survival.

Detailed description:
Surgical resection is a cornerstone of standard-of-care treatment for early-stage non-small cell lung carcinoma (NSCLC) and renal cell carcinoma (RCC). Yet despite optimal treatment, many of these patients will develop cancer recurrence within the first few years. For example, the 5-year survival rate for patients with stage I/II NSCLC is only around 55%. As a result, more effective treatments that decrease cancer recurrence and increase survival are still needed.

Surgery induces inflammation, immunosuppression and angiogenesis. Although these processes are important for wound healing in response to tissue injury caused by surgery, they also support the survival, growth and dissemination of any remaining cancer cells and can lead to systemic recurrence soon after surgery. Surgical trauma increases the production of prostaglandins and thromboxanes, which have tumor-promoting and immunosuppressive activities, and reduces the activity of natural killer cells, which impairs the ability of the immune system to keep cancer cells in check. However, if given just before tissue injury, non-steroidal anti-inflammatory drugs (NSAIDs) may be able to block the production of prostaglandins/thromboxanes and boost the activity of natural killer cells, and thereby decrease the risk of cancer recurrence. NSAIDs such as ketorolac are already routinely given to cancer patients postoperatively for pain management and are sometimes given intraoperatively (immediately before or during surgery) to prevent postoperative pain. A retrospective clinical analysis found that intraoperative intravenous ketorolac or diclofenac (another NSAID), when added to standard of care for patients with stage I/II NSCLC, was associated with decreased risks of distant recurrence and mortality.

In this study, patients with NSCLC or RCC will be screened and recruited during the preoperative period by the responsible medical and surgical team. Participants will be randomized on the day of surgery to either the preoperative ketorolac group or a concurrent control group who will not receive preincisional ketorolac. Participants will be followed for 28 days.

Arms: arm 1: Participants randomized to receive ketorolac prior to surgery for stage I/II non-small cell lung carcinoma (NSCLC). Participants receive standard-of-care surgery. Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia is administered. arm 2: Participants randomized to the control group receiving the standard of care during surgery for stage I/II non-small cell lung carcinoma (NSCLC). Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia is administered. The concurrent control group is to obtain untreated biologic samples for biologic correlative studies and secondary endpoints. arm 3: Participants randomized to receive ketorolac prior to surgery for stage III renal cell carcinoma (RCC). Participants receive standard-of-care surgery. Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia is administered. arm 4: Participants randomized to the control group receiving the standard of care during surgery for stage III renal cell carcinoma (RCC). Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia is administered. The concurrent control group is to obtain untreated biologic samples for biologic correlative studies and secondary endpoints.
Interventions: intervention 1: Preoperative Ketorolac
Intervention descriptions: intervention 1: 30 mg ketorolac will be administered intravenously 30 minutes prior to incision.

Protocol documents:
Prot_SAP_000.pdf: 
Study Protocol 
 
TITLE: A Pilot Study of Biomarker Evaluation and Safety of Pre-Incisional 
Ketorolac for Patients Undergoing Surgical Resection for Non-Small Cell 
Lung Cancer and Renal Cell Carcinoma 
 
NCT NUMBER: NCT04495894 
 
Protocol Date: February 23, 2024 


A Pilot Study of Biomarker Evaluation and Safety of Pre-Incisional Ketorolac for Patients 
Undergoing Surgical Resection for Non-Small Cell Lung Cancer and Renal Cell Carcinoma 
Page 1 of 19
Protocol Version: 7.0 (23 FEB 2024)
PROTOCOL TITLE: A Pilot Study of Biomarker Evaluation and Safety of Pre-Incisional Ketorolac 
for Patients Undergoing Surgical Resection for Non-Small Cell Lung Cancer and Renal Cell 
Carcinoma
PRINCIPAL INVESTIGATORS:
Onkar V. Khullar, MD
Assistant Professor of Surgery
Division of Cardiothoracic Surgery
(404) 686-2515
OKHULLA@emory.edu
Viraj A. Master, MD, PhD
Professor of Urology
Department of Urology
(404) 778-4898
vmaster@emory.edu 
CO-INVESTIGATORS:
Haydn Kissick, PhD
Assistant Professor
Department of Urology
Department of Microbiology and Immunology
Manoj Bhasin, PhD
Associate Professor
Department of Biomedical Informatics
Yuan Liu, PhD
Associate Research Professor
Department of Biostatistics and Bioinformatics
Rollins School of Public Health
VERSION: 7.0 (23 FEB 2024)
FUNDING SOURCE: Morningside Center 


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Protocol Version: 7.0 (23 FEB 2024)
REVISION HISTORY
Revision #
Version 
Date
Summary of Changes
1.0
26Mar2020
First version submitted to Emory IRB
2.0
27Aug2020
Second version with minor clarifications and specification 
of sample collection visit windows. 
3.0
24Nov2020
Third version with minor dosing clarification. 
4.0
19Feb2021
Fourth version with minor exclusion eGFR level changes
5.0
27Jan2022
Fifth version with increased overall enrollment goal of up 
to 100 patients to account for screen fails and/or 
withdrawals 
6.0
31 Mar 2022
Sixth version with minor clarification regarding tissue 
collection including malignant and benign tissue. 
7.0
23 FEB 2024
Ceasing enrolment for the Cardiothoracic group


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Table of Contents
1.
Study Summary .......................................................................................................................4
2.
Objectives................................................................................................................................4
3.
Introduction and Background....................................................................................................4
4.
Study Endpoints ......................................................................................................................4
5.
Study Intervention/Investigational Agent...............................................................................4
6.
Procedures Involved................................................................................................................5
7.
Data and Specimen Banking....................................................................................................6
8.
Sharing of Results with Participants........................................................................................6
9.
Study Timelines .......................................................................................................................6
10.
Inclusion and Exclusion Criteria...........................................................................................7
11.
Vulnerable Populations .......................................................................................................7
12.
Local Number of Participants ..............................................................................................7
13.
Recruitment Methods..........................................................................................................8
14.
Withdrawal of Participants..................................................................................................8
15.
Risks to Participants.............................................................................................................8
16.
Potential Benefits to Participants........................................................................................9
17.
Data Management and Confidentiality ...............................................................................9
18.
Provisions to Monitor the Data to Ensure the Safety of Participants..................................9
19.
Provisions to Protect the Privacy Interests of Participants................................................10
20.
Economic Burden to Participants ......................................................................................10
21.
Consent Process.................................................................................................................10
22.
Setting................................................................................................................................13
23.
Resources Available...........................................................................................................13
24.
Multi-Site Research when Emory is the Lead Site .............................................................13
25.
References.........................................................................................................................14


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1. Study Summary
Study Title
A Pilot Study of Biomarker Evaluation and Safety of 
Pre-Incisional Ketorolac for Patients Undergoing 
Surgical Resection for Non-Small Cell Lung Cancer and 
Renal Cell Carcinoma
Study Design
PATIENT REGISTRATION/RANDOMIZATION
Patients will be screened and recruited during the pre-
operative period by the responsible medical and 
surgical team. Blood will be drawn pre-operatively and 
then at the end of the surgical procedure. Patients who 
are eligible to be included will be fully informed, 
consented for additional blood draws and will have the 
opportunity to ask any questions they may have. 
Patients will be randomized to either pre-operative 
Ketorolac group or a concurrent control group who 
will not receive pre-incisional ketorolac. The 
concurrent control group is to obtain untreated biologic 
samples for biologic correlative studies and secondary 
endpoints. These patients will not be compared to the 
investigational cohort in regards to the primary 
endpoint of safety. Patients will be randomized on the 
day of surgery to either the experimental or control 
arms.  A total of 56 patients will be enrolled into the 
experimental arm (28 per disease site). About 10 
patients will be allocated randomly into the concurrent 
control group for each disease site separately, for a 
total of 76 patients enrolled. The enrolment for 
NSCLC will cease at total of 28 patients consented 
with total study enrolment goal of 79 Up to 80 patients 
may be consented on study to account for screen fails 
and/or withdrawals.
Primary Objective
To test the safety of a single pre-incisional dose of 30 
mg ketorolac in patients undergoing surgery for stage 
I/II NSCLC and stage III RCC, as these are the stages of 
cancer most likely to develop a recurrence while still 
noting a benefit from the ketorolac.
Secondary Objective(s)
To evaluate blood and tissue samples pre- and post-
operatively to assess the impact of ketorolac on key 


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inflammatory biomarkers using a standard cytokine 
panel.
Research 
Intervention(s)/Interactions
STUDY PROCEDURES
Surgical Resection
All patients will receive standard-of-care surgery. 
Open, video-assisted thoracic surgery, laparoscopy, or 
robotic surgery are allowed. Standard anesthesia will 
be administered.
Ketorolac 
30 mg ketorolac will be administered intravenously 
during the induction of anesthesia (pre-incision). 
Ketorolac administration will not be permitted during 
the operation. Patients randomized to the control 
group will not receive Ketorolac. 
Study Population
See Inclusion Criteria and Exclusion Criteria.
Sample Size
See Statistical Consideration
Study Duration for 
individual participants
2 years
Study Specific 
Abbreviations/ Definitions 
N/A
Funding Source (if any)
Morningside Center
2. Objectives
2.1
Primary Objective
To test the safety of a single pre-incisional dose of 30 mg ketorolac in patients 
undergoing surgery for stage I/II NSCLC and stage III RCC, as these are the stages 
of cancer most likely to develop a recurrence while still noting a benefit from the 
ketorolac.
2.2
Secondary Objective
To evaluate blood and tissue samples pre- and post-operatively to assess the 
impact of ketorolac on key inflammatory biomarkers using a standard cytokine 
panel.
3. Introduction and Background
Surgical resection is a cornerstone of standard-of-care treatment for early-stage non-small cell 
lung carcinoma (NSCLC) and renal cell carcinoma (RCC). Yet despite optimal treatment, many of 
these patients will develop cancer recurrence within the first few years. For example, the 5-year 


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survival rate for patients with stage I/II NSCLC is only around 55%.1 As a result, more effective 
treatments that decrease cancer recurrence and increase survival are still needed.
Surgery induces inflammation, immunosuppression and angiogenesis. Although these processes 
are important for wound healing in response to tissue injury caused by surgery, they also support 
the survival, growth and dissemination of any remaining cancer cells and can lead to systemic 
recurrence soon after surgery. Surgical trauma increases the production of prostaglandins and 
thromboxanes, which have tumor-promoting and immunosuppressive activities, and reduces the 
activity of natural killer cells, which impairs the ability of the immune system to keep cancer cells 
in check. However, if given just before tissue injury, non-steroidal anti-inflammatory drugs 
(NSAIDs) may be able to block the production of prostaglandins/thromboxanes and boost the 
activity of natural killer cells, and thereby decrease the risk of cancer recurrence. Indeed, NSAIDs 
have anticancer effects in animal models and humans.2-5 For example, in one study, the 20-year 
risk of cancer-related death was significantly lower after administration of daily aspirin (HR 0.80, 
p<0.0001).2
NSAIDs such as ketorolac are already routinely given to cancer patients post-operatively for pain 
management and are sometimes given intra-operatively (immediately before or during surgery) 
to prevent post-operative pain. A retrospective clinical analysis found that intra-operative 
intravenous ketorolac or diclofenac (another NSAID), when added to standard of care for patients 
with stage I/II NSCLC, was associated with decreased risks of distant recurrence (HR = 0.50; 95% 
CI 0.24-1.00; P = 0.05) and mortality (HR = 0.64; 95% CI 0.42-0.96; P = 0.03) (Figure 1).6 Similar 
results were seen in renal cell carcinoma (RCC). 
Figure 1. Kaplan–Meier curves of overall survival for 255 patients receiving or not an 
NSAID (ketorolac or diclofenac) intra-operatively during NSCLC surgery. Univariate 
analysis by log-rank test. Figure from 6. 


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The effect of intra-operative NSAIDs may be even more prominent in patients with pre-operative 
inflammation, which is associated with a greater risk of early recurrence and mortality.6 
Moreover, recent data indicates that pre-operative, but not post-operative, ketorolac 
administration can eliminate micrometastatic disease in animal lung and breast cancer resection 
models and create long-lasting T cell immunity.7 Thus in addition to safety and feasibility, we will 
assess whether there is evidence of a tumor directed T-cell response in patients who receive pre-
operative ketorolac.
We do note a recently published randomized phase III study in breast cancer failed to identify a 
reduction in recurrence rates in high-risk breast cancer patients8, and did not support 
retrospective data which did show a benefit.9 Though many possibilities exist for the negative 
results of this most recent study, one possibility is that chemotherapy was utilized in the majority 
of the patients, and arms were somewhat imbalanced. This may have negated the effect of the 
ketorolac, as noted in our preclinical animal studies.7
Given these overall findings, there is significant promise in the use of preoperative ketorolac 
to decrease the inflammatory response after surgical resection of tumors, thereby potentially 
reducing the risk of distant metastatic tumor spread and improving survival. These results 
could potentially be applied to any number of tumor sites. However, ketorolac and other 
NSAIDS inhibit platelet function by blocking cyclooxygenase enzymes and the formation of 
thromboxane A2, resulting in potentially higher risk for postoperative bleeding or result in 
higher rates of postoperative renal failure.10,11 While the risk of such complications after a single 
dose of ketorolac is likely low, the safety of a preoperative dose of ketorolac prior to major 
surgical resection needs to be assessed prior to proceeding with a larger phase II study designed 
to evaluate traditional efficacy endpoints such as recurrence and overall survival. Additionally, 
the proposed mechanism that ketorolac effect is T-cell dependent and contributes directly to 
anti-tumor activity via reduction of postoperative inflammation can be further studied. Blood 
and tissue samples from patients enrolled in this study will be analyzed to determine if the 
effect of ketorolac is more prominent in patients with high pre-operative inflammation.
4. Study Endpoints 
4.1
Primary Safety Endpoints
Incidence of clinically significant pre-discharge (both intra- and post-operative) 
blood transfusion, clinically significant hematoma development, or return to the 
operating room for bleeding; post-operative renal failure; and post-operative 
morbidity rates.
4.2
Secondary Endpoints


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A number of exploratory biological correlative studies including transcriptome 
analysis, flow cytometry, TCR sequencing and single cell RNA Seq to evaluate the 
effects of ketorolac on immune response pathways.
5. Study Intervention/Investigational Agent
5.1
Surgical Resection
All patients will receive standard-of-care surgery. Open, video-assisted thoracic surgery, 
laparoscopy, or robotic surgery are allowed. Standard anesthesia will be administered.
5.2
Ketorolac 
30 mg ketorolac will be administered intravenously during the induction of anesthesia 
(pre-incision). Ketorolac administration will not be permitted during the operation. 
6. Procedures Involved
6.1
Study Calendar
Tests and 
Observations
Within 
60 
days 
prior 
to reg.
Before 
surgery at 
preoperative 
visit
Day of 
surgery
(Day 0) 
3 days 
7 days 
(+/- 2 
days)
28 days 
(+/- 7 
days)
1 and 2 
years
(+/- 3 
months)
History, physical, 
creatinine test, 
ECOG/Zubrod PS
X
 
 
PET/CT, CT, or 
MRI scan head, 
neck, chest, or 
abdomen per 
standard of care
X
 
 
 
Charlson 
comorbidity 
index
 
X
 
 
Blood samples 
for biomarker 
analyses*
 
X
X
X
X
X
Fresh tissue 
collection
X
Adverse event 
assessment
 
X
X 
X
X


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Protocol Version: 7.0 (23 FEB 2024)
Chart review or 
patient contact 
for survival 
assessment 
X
*See section 7.1 Biological Correlative Studies
6.2
Procedures
6.2.1
Surgical Resection
All patients will receive standard-of-care surgery. Open, video-assisted thoracic 
surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia will be 
administered.
6.2.2
Ketorolac 
30 mg ketorolac will be administered intravenously during the induction of 
anesthesia (pre-incision). Ketorolac administration will not be permitted during 
the operation.
6.3
Follow-up
After completion of protocol therapy, patients will be monitored for peri-
operative adverse events for up to 90 days after surgery, per routine standard of 
care for the respective surgical procedure. Patients with benign disease on 
pathology will still be followed for adverse events for 90 days after surgery, 
however will not be counted towards the patients analyzed for the study.
Patient charts, institutional renal cell and thoracic surgical databases (Society of 
Thoracic Surgeons Database), and the Georgia Cancer Registry through the 
Winship Cancer Institute will be queried to determine patient vital status, status 
of tumor recurrence if any, and if applicable, cause of death, at 1- and 2-years 
post-surgery. Only RCC patients will be followed up at 1- and 2-years post-
surgery. All study follow-up will cease for NSCLC patients.
7. Data and Specimen Banking 
7.1
Biological Correlative Studies
The specific effects of ketorolac on the host immune system are not known. It is hypothesized 
that pre-operative ketorolac will enhance anti-tumor immunity and result in activation of tumor-
specific T cell responses, as has been noted in our preclinical studies7. To verify this, we will collect 
tissue samples, including surrounding benign and malignant tissue as part of the standard surgical 
procedure, and peripheral blood at pre-specified time-points. The following samples will be 
collected from all patients on this trial:


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1. Tumor tissue at the time of surgery - Tissue will be collected from patients at the time of 
surgery by clinical research coordinators from the Clinical Research Unit and taken to Dr. 
Haydn Kissick's lab if adequate tissue is available after all necessary clinical samples are 
obtained as determined by the pathologist. Tissue analysis will be performed on 
malignant and benign tissue. 
2. Serum and PBMCs before and at time points after surgery - Blood will be collected in CPT 
from patients at the time of surgery and postoperatively, as delineated in the timeline, by 
clinical research coordinators.
The following studies are planned in the bio-specimens collected: 1. Flow cytometry (at least to 
assess proliferating and activated T-cells in blood); 2. TCR sequencing to assess diversity of the T 
cell repertoire intra tumorally and in blood; and 3. Single cell RNA Seq in blood. Samples will be 
suitably prepared to allow for this at a future date. Collectively these assays will provide evidence 
for whether pre-op ketorolac can unleash post-operative anti-tumor T cell response in humans, 
thus extending the mouse data above. In addition, we will measure NLR, CRP, and IL-6 – all of 
which have been correlated to prognosis in a number of tumor types at baseline and some of 
which have been correlated to recurrence outcomes. Additional exploratory studies may also be 
conducted based on the results of these studies. Peripheral blood mononuclear cells (PBMCs) 
and plasma will be isolated from CPTs and cryopreserved. The correlative work will be conducted 
in the lab of Rafi Ahmed, Manoj Bhasin and Haydin Kissick.
Tissue analysis: In this proposal, we will measure how organization of immune cells in the tumor 
change after treatment. The tumor architecture and immune organization will be examined via 
IF and this imaging data will be quantitatively analyzed. We will determine the relative infiltration 
of stem-like T-cells, effector-like T-cells, and DCs, lymphatic and blood vessels. We will measure 
the distance between cells, and quantify their aggregation. We will specifically quantitate regions 
of sufficient antigen presenting density (5 APCs/100um2) that are generated following 
implantation of the niche, and how these regions are located relative to the implant. A specific 
focus of this work will be how lymphatic and vasculature is altered before and after treatment 
and how this correlates with response to therapy.
Serum analysis: We will measure NLR, CRP, and IL-6 – all of which have been correlated to 
prognosis in a number of tumor types at baseline and some of which have been correlated to 
recurrence outcomes.
PBMC analysis: In ongoing work we have collected blood and tissue from patients 
receiving checkpoint blockade therapies at Emory and studied the immune response of 
these patients. We have found that in the blood of patients that have a clinical response 
to checkpoint therapy, there is a proliferative burst of newly generated effector CD8 T-
cells in the blood. In comparison, patients that do not have clinical response to the 
treatment fail to generate this population of cells. This marker has significant predictive 
power to identify which patients will respond after the first treatment cycle with PD-1 


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blockade. In this proposal we will determine if measuring this marker after surgery and 
treatment with Ketorolac is associated with improved response to treatment.
7.2
Blood Sample Collection
Blood samples will be obtained before surgery in the preoperative holding area at the time of 
routine IV placement and at day 3 after surgical resection. Additional samples will be collected at 
Day 7 (+/- 2) and Day 28 (+/- 7) post-surgery. Lung resection and nephrectomy patients are 
typically admitted after surgery. Therefore day 3 blood samples will be obtained while patients 
are admitted to the hospital. However, if patients are discharged prior to day 3 samples will be 
collected via mobile blood draw services at patient’s home. In addition, study team may use 
mobile blood draw services to collect some postoperative samples at patients’ homes. Tumor 
samples will be collected from pathology at the time of resection.
CPT tubes should be at stored at room temperature following blood collection. CPT tubes should 
be inverted approximately 10 times after blood collection and kept rocking until processing. CPT 
tubes should be processed the same day.
Blood 
specimens 
taken from
Collected when 
Submitted as
PBMCs and 
plasma: 3 CPTs 
(8 mL each) of 
whole blood for 
collection of 
plasma and 
PBMCs
Pre-surgery: at preoperative anesthesia 
visit and the day of surgery
Post-surgery: 
Post-operative day 2-3 while in the 
hospital
Between post-operative day 5-20, 
either prior to discharge or at 
postoperative clinic visit
Frozen plasma samples 
containing 2 mL per 
aliquot in 2 mL 
cryovials: Cryopreserved 
PBMCs containing 107 
PBMCs per aliquot in 2 
mL cryovials
8. Sharing of Results with Participants
There are no plans to share results with the participants.
9. Study Timelines
The study will be closed to enrollment for all patients. Only RCC participants are 
expected to participate in the study for 2 years. All study related assessments and 
activities to cease for NSCLC participants. The estimated date for investigators to 
complete this study is March 1, 2025.


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10. Inclusion and Exclusion Criteria
SUBJECT ELIGIBILITY
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and 
exclusion criteria to be registered to the study. Study treatment may not begin 
until a subject is registered.
10.1
Inclusion Criteria
10.1.1 Age ≥ 18 years and ≤ 80 years.
10.1.2 Pathology-proven or suspected stage 1 or 2 NSCLC and Stage 3 T3N0 RCC, 
that require surgical resection as the treatment of choice 
10.1.3 ECOG performance status (PS) 0, 1, or 2.
10.1.4 Ability to understand and the willingness to sign an informed written 
consent.
10.2
Exclusion Criteria
10.2.1 Individuals with pure lung ground-glass opacity (GGO) lesions or mixed 
GGO with <50% solid component. 
10.2.2 Patients undergoing pneumonectomy
10.2.3 History of cancer in the 3 years prior to surgery (except for basal-cell 
carcinoma of the skin or cervical neoplasia).
10.2.4 Contraindication for NSAIDs (peptic ulcer disease, pre-operative chronic 
kidney disease with eGFR <45 measured with the MDRD equation used widely, 
including at Emory), allergies or intolerance to NSAIDs, coagulation disorder, or 
age > 80 years). 
10.2.5 Having taken an NSAID within 5 days prior to surgery. 
10.2.6 Immunocompromised status
10.2.7 Refusal or inability to understand the protocol and consent form or to 
receive follow-up in line with the recommendations.
10.2.8 Preoperative hemoglobin < 9.0
11. Local Number of Participants
Up to 80 patients will be enrolled locally. 
12. Recruitment Methods


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Participants may be identified by review of medical records or physician referral. After 
an investigator introduces the study to the participant, the consent form may be given 
in person, mailed, emailed, or sent to the participant through EPIC or the Emory Patient 
Portal. The study team will follow up with the participant through the methods of 
communication listed above, by phone, and/or in person to communicate with the 
participant about the study. The participant will be given time to read the consent form 
and ask questions. A member of the study team will reach out to the participant to 
make sure the participant understands all aspects of the study and the participant is 
ready to sign the consent documentation. The participant may sign the consent forms in 
a private setting at Emory. Also, the participant has the option to consent by mail. 
Subjects with LEP may be enrolled and study team members will use Emory IRB 
approved shortforms to conduct the consent process. Participants will not receive any 
payment or reimbursement for this study. Study enrolment will cease for NSCLC 
participates.
13. Withdrawal of Participants
Participation in this study is completely voluntary and participants can withdraw at any 
time without any consequences. Participants can also be withdrawn from the study 
without their consent if their safety is at risk. This is unanticipated for this study. The 
revocation form specifies the procedures for participants withdrawing from the study. 
14. Risks to Participants
Expected Adverse Events - Ketorolac
The expected incidence of postoperative adverse events attributable to a single 
preoperative ketorolac dose is expected to be very low. Known gastrointestinal side 
effects of ketorolac include (gastritis, gastroduodenal ulcer), pulmonary side effects 
(bronchospasm) and renal side effects (kidney failure) and typically arise with long-term 
use.11, 12 Ketorolac has been routinely used for postoperative analgesia in each of 
disease sites being studies. For example, Freedland, et al., in a retrospective review of 
198 patients undergoing donor nephrectomy, found no increased risk of complications 
or worsening of long-term renal function with postoperative ketorolac use.13 Similar 
results have been seen after lung and other cancer resections with postoperative 
use.14-16 Non-selective NSAIDs, such as ketorolac, are known to have the potential to 
affect platelet function. This does not prevent them from being routinely used after 
numerous surgical procedures including trauma surgery. However, pre-/intra-operative 
use of ketorolac has not been studied in lung and kidney surgical patients. Therefore, 
intra- and post-operative and transfusion rates will be monitored as the primary 
endpoint for this study. Operative blood loss will also be monitored. Subjects will also be 
monitored for change in decline in eGFR greater than expected for the procedure.  For 
example, for kidney removal, we expect eGFR to decline 50%, and consider this 


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expected.  However, it if declines by more than 75%, we would consider this 
unexpected, possibly due to ketorolac.
15. Potential Benefits to Participants
There is significant promise in the use of preoperative ketorolac to decrease the 
inflammatory response after surgical resection of tumors, thereby potentially reducing 
the risk of distant metastatic tumor spread and improving survival.
16. Data Management and Confidentiality
16.1 Data and Safety Monitoring
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer 
Institute will provide oversight for the conduct of this study.  The DSMC 
functions independently within Winship Cancer Institute to conduct internal 
monitoring functions to ensure that research being conducted by Winship 
Cancer Institute Investigators produces high-quality scientific data in a manner 
consistent with good clinical practice (GCP) and appropriate regulations that 
govern clinical research.    Depending on the risk level of the protocol, the DSMC 
review may occur every 6 months or annually.  For studies deemed High Risk, 
initial study monitoring will occur within 6 months from the date of the first 
subject accrued, with 2 of the first 5 subjects being reviewed.  For studies 
deemed Moderate Risk, initial study monitoring will occur within 1 year from the 
date of the first subject accrued, with 2 of the first 5 subjects being reviewed.  
Subsequent monitoring will occur in routine intervals per the Winship Data and 
Safety Monitoring Plan (DSMP). 
The DSMC will review pertinent aspects of the study to assess subject safety, 
compliance with the protocol, data collection, and risk-benefit ratio. Specifically, 
the Winship Cancer Institute Internal Monitors assigned to the DSMC may verify 
informed consent, eligibility, data entry, accuracy and availability of source 
documents, AEs/SAEs, and essential regulatory documents.  Following the 
monitoring review, monitors will provide a preliminary report of monitoring 
findings to the PI and other pertinent individuals involved in the conduct of the 
study.  The PI is required to address and respond to all the deficiencies noted in 
the preliminary report.  Prior to the completion of the final summary report, 
monitors will discuss the preliminary report responses with the PI and other 
team members (when appropriate).  A final monitoring summary report will then 
be prepared by the monitor.  Final DSMC review will include the final monitoring 
summary report with corresponding PI response, submitted CAPA (when 


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applicable), PI Summary statement, and available aggregate toxicity and safety 
data.
The DSMC will render a recommendation and rating based on the overall trial 
conduct.  The PI is responsible for ensuring that instances of egregious data 
insufficiencies are reported to the IRB.  Continuing Review submissions will 
include the DSMC recommendation letter.  Should any revisions be made to the 
protocol-specific monitoring plan after initial DSMC approval, the PI will be 
responsible for notifying the DSMC of such changes.  The Committee reserves 
the right to conduct additional audits if necessary.
There is no dose escalation planned for this study. The procedures to assure data 
integrity and protocol adherence are standard of care procedures for this study. 
Regular data verification and protocol adherence will take place in real time. The 
standard of care labs will be collected and the PI will review and analyze the 
results in real time. All data will be recorded and all adverse events will be 
graded and reported in real time using the CTCAE criteria for evaluation. The 
oversight of the study team be carried out by the PI reviewing data in real time 
and results being discussed at the GU working group meetings as necessary. The 
evaluation of kidney function and labs is standard of care. The study team will 
not need to be trained on study procedures because there are no new 
procedures being done that are not part of the standard of care.  
16.2 Statistical Consideration
16.2.1 Sample size determination
It is a pilot study that aims to monitor the hemorrhage side effects who received 
Ketorolac pre-operatively with the primary safety endpoint being pre-discharge blood 
transfusion. According to the historical data, among 3280 nephrectomy cases during 
2015-2020 in Emory, 20% need a blood transfusion before the discharge, and the mean 
number of units transfused is 0.286 (standard deviation = 0.12). Among 1212 
thoracotomy cases during 2014 -2020 in Emory, 3.4% need a blood transfusion before 
the discharge, and the mean number of units transfused is 0.098 (standard deviation = 
0.075). We anticipate a similar safety profile among the patients who received the pre-
operative Ketorolac in this study. A sample size of 50 (25 patients in each disease site) 
produces a one-sided 90% confidence interval with an upper limit of 0.12 (the distance 
from the mean number of units transfused to the upper limit = 0.02) for thoracotomy. 
For nephrectomy, the upper limit of a one-sided 90% confidence interval would be 
0.318 (the distance from the mean number of units transfused to the upper limit = 
0.032). To account for a possible 10%, drop off, we will plan to enroll 28 patients in each 
disease type.


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16.2.2 Stopping Rule
The PIs will monitor the blood transfusion ordered and the units transfused before 
patients’ discharge. In any case, blood transfusion with more than 2 units (BT2U) 
happens, the trial will pause to examine the cause and decide whether to continue or 
terminate the trial due to the safety concern. The trial will be terminated if the 
accumulative relevant BT2U number reaches to six for nephrectomy (24%) or two for 
thoracotomy (8%). The stopping rule is to stop the trial early due to any high chance of 
toxicity. 
16.2.3 Analysis of safety data
All subjects who receive Ketorolac will be included in the summaries and listings of 
safety data. Overall safety profile will be characterized by type, frequency, severity, 
timing, during, and relationship of Ketorolac. The rate of pre-discharge blood 
transfusion and the mean blood unit transfused will be summarize by frequency and 
proportion with 95% confidence interval for the rate of AEs, and mean (range) and 95% 
Wald confidence interval.
16.2.4 Analysis of the secondary endpoints
For all biomarkers, descriptive statistics (means, medians, standard deviations, 
interquartile range) and graphical displays will be used to characterize central tendency 
and variability over time. Values will be log transformed as appropriate to reflect 
biologic plausibility.
16.3
EVALUATION OF OUTCOMES
All patients will be followed for adverse events including surgical morbidity and 
mortality for 90 days after surgery. Toxicity will be graded according to the NCI CTC 
version 4.4. The rates of all Grade 3-5 adverse events during or within 90 days of surgery 
will be tested for equality using a two-sided chi-square test or Fisher’s exact test with a 
0.05 significance level. 
16.3.1 Overall safety assessment
The primary objective is to assess the safety data by using ketorolac pre-operatively, and 
we plan to longitudinally collect safety data from each patient. The study team will meet 
on a regular basis to review safety events and make decision about trial stopping based 
on the safety concerns.
16.3.2 Bleeding
Post-operative bleeding will be assessed as follows:
16.3.2.1
Need for return to the operating room for bleeding as determined by the 
treating surgeon


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16.3.2.2
Need for transfusion, > 2units of blood, which are not related to vascular 
injury due to technical considerations or complications, as determined by the operating 
surgeon.
16.3.2.3
Hemoglobin < 7.0 postoperatively, regardless of whether transfusion has 
occurred.
17. Provisions to Protect the Privacy Interests of Participants
All actions described in HIPAA section of consent form will be taken to protect the 
privacy of participants. The study will be explained to participants and they will have the 
opportunity to ask as many questions as necessary to feel comfortable consenting to 
participate in the study.
18. Economic Burden to Participants
There are no additional costs that participants will be responsible for if they participate 
in this research study.
19. Consent Process
Participants may be identified by review of medical records or physician referral. After 
an investigator introduces the study to the participant, the consent form may be given 
in person, mailed, emailed, or sent to the participant through PowerChart or the Emory 
Patient Portal. The study information, such as the consent form, may be sent to the 
patient using an encrypted email. The study team will follow up with the participant 
through the methods of communication listed above, by phone, Emory licensed Zoom, 
and/or in person to communicate with the participant about the study. The study team 
member will confirm with the participant that they received all pages of the consent 
form. The participant will be given time to read the consent form and ask questions. A 
member of the study team will reach out to the participant to make sure the participant 
understands all aspects of the study and the participant is ready to sign the consent 
documentation. Identity of each participant will be confirmed prior to consent. The 
informed consent discussion can take place in person or via phone or Emory licensed 
Zoom. The consent process may take place in the ways described below.
1. The participant may sign the consent form in a private setting at Emory.
2. The participant may print the consent form at home and sign with a wet ink 
signature. The participant can send the consent form back to the study team using 
the following methods:
a. The participant will scan and send the signature pages of the consent form 
back to the study team via email
b. The participant may take pictures of the signature pages of the consent form 
and send it back to the study team via email


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c.
The participant can mail the wet ink signed pages of the consent form to the 
study team.
Participants will be given a copy of the consent form. Participants with LEP may be 
enrolled and study team members will use Emory IRB approved short forms to conduct 
the consent process. There will be a translator present when the study team enrolls a 
participant with LEP.
20. Setting
Subjects will be identified prior to surgery. They may be consented in a clinic or hospital 
setting.
21. Resources Available
There are hundreds of resections for Non-Small Cell Lung Cancer and Renal Cell 
Carcinoma each year. Within 5 years of recruiting, the goal of 76 patients enrolled is 
feasible. 50% of one full time research coordinator’s effort will be devoted to this trial 
annually. Medical and psychological resources that participants might need as a result of 
an anticipated consequences of the human research are available at Emory.
A dedicated clinical research team will be available to assist in proper conduct of this 
research study. There will be extensive documentation of training for study personnel. 
This will be documented on training forms, delegation of authority forms, the 1572, and 
other documents. Training is ongoing and will be updated as needed.
22. References
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Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the 
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of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. 
Lancet. 2011;378(9809):2081-2087.
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Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin 
on long-term risk of death due to cancer: analysis of individual patient data from 
randomised trials. Lancet. 2011;377(9759):31-41.
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Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer 
incidence, mortality, and non-vascular death: analysis of the time course of risks and 
benefits in 51 randomised controlled trials. Lancet. 2012;379(9826):1602-1612.


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Forget P, Machiels JP, Coulie PG, et al. Neutrophil:lymphocyte ratio and intraoperative 
use of ketorolac or diclofenac are prognostic factors in different cohorts of patients 
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Panigrahy D, Gartung A, Yang J, et al. Preoperative stimulation of resolution and 
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Forget P, Bouche G, Duhoux FP, et al. Intraoperative ketorolac in high-risk breast cancer 
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Forget P, Vandenhende J, Berliere M, et al. Do intraoperative analgesics influence breast 
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Schafer AI. Effects of nonsteroidal antiinflammatory drugs on platelet function and 
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Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual non-steroidal 
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Freedland SJ, Blanco-Yarosh M, Sun JC, et al. Ketorolac-based analgesia improves 
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Kelley BP, Chung KC, Chung TT, et al. Postoperative Ketorolac in Breast and Body 
Contouring Procedures: A Nationwide Claims Analysis. Plast Reconstr Surg. 
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Forrest JB, Camu F, Greer IA, et al. Ketorolac, diclofenac, and ketoprofen are equally safe 
for pain relief after major surgery. Br J Anaesth. 2002;88(2):227-233.
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