Pre-Incisional Ketorolac for Patients Undergoing Surgery for Non-Small Cell Lung Cancer and Renal Cell Carcinoma

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

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. A total of 56 patients (28 per disease site) will be enrolled into the experimental arm and will receive ketorolac prior to surgery. About 10 patients will be allocated randomly into a control group, for each disease site, for a total of 76 patients enrolled. The 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.

Study Overview

• Status: Recruiting
• Conditions: Renal Cell Carcinoma; Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Preoperative Ketorolac

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.

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.

Patients will be screened and recruited during the preoperative period by the responsible medical and surgical team. Blood will be drawn preoperatively and then at the end of the surgical procedure. Participants will be randomized to either preoperative ketorolac group or a concurrent control group who will not receive preincisional 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 and participants will be followed or 28 days. Medical records will be reviewed at 1 and 2 years post-surgery for survival assessment.

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Viraj Master, MD, PhD; Phone Number: 404-778-4898; Email: vmaster@emory.edu

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Recruiting
      • Emory University Hospital Midtown
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory Clinic
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Winship Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pathology-proven or suspected stage 1 or 2 NSCLC and Stage 3 tumor stage 3, node stage 0 (T3N0) RCC, that require surgical resection as the treatment of choice
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Ability to understand and the willingness to sign an informed written consent

Exclusion Criteria:

• Individuals with pure lung ground-glass opacity (GGO) lesions or mixed GGO with <50% solid component
• Patients undergoing pneumonectomy
• History of cancer in the 3 years prior to surgery (except for basal-cell carcinoma of the skin or cervical neoplasia).
• Contraindication for NSAIDs, including peptic ulcer disease, preoperative chronic kidney disease with estimated glomerular filtration rate (eGFR) <45, allergies or intolerance to NSAIDs, coagulation disorder, or age > 80 years
• Having taken an NSAID within 5 days prior to surgery
• Immunocompromised status
• Refusal or inability to understand the protocol and consent form or to receive follow-up in line with the recommendations
• Preoperative hemoglobin < 9.0

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Preoperative Ketorolac; Participants randomized to receive ketorolac prior to surgery for stage I/II NSCLC and stage III RCC. Participants will receive standard-of-care surgery. Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia will be administered.	Drug: Preoperative Ketorolac; 30 mg ketorolac will be administered intravenously 30 minutes prior to incision.; Other Names: Acular; Acuvail
No Intervention: Control Group; Participants randomized to the control group receiving the standard of care during surgery for stage I/II NSCLC and stage III RCC. Open, video-assisted thoracic surgery, laparoscopy, or robotic surgery are allowed. Standard anesthesia will be administered. The concurrent control group is to obtain untreated biologic samples for biologic correlative studies and secondary endpoints.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Blood Transfusion Among Ketorolac Group	Hemorrhagic side effects among participants receiving ketorolac preoperatively will be assessed as the need for blood transfusions before being discharged from the hospital after surgery. The need for a blood transfusion is defined as greater than two units of blood, which are not related to vascular injury due to technical considerations or complications, as determined by the operating surgeon.	Prior to Hospital Discharge (generally up to 7 days post surgery)
Incidence of Clinically Significant Hematoma Development Among Ketorolac Group	Significant hematoma development will be assessed among participants receiving ketorolac.	Prior to Hospital Discharge (generally up to 7 days post surgery)
Incidence of Return to the Operating Room for Bleeding Among Ketorolac Group	The need for returning to the operating room for bleeding, as determined by the treating surgeon, will be assessed among participants receiving ketorolac.	Prior to Hospital Discharge (generally up to 7 days post surgery)
Incidence of Postoperative Renal Failure Among Ketorolac Group	Postoperative renal failure among participants receiving ketorolac will be assessed.	Prior to Hospital Discharge (generally up to 7 days post surgery)
Incidence of Postoperative Morbidity Rate Among Ketorolac Group	Postoperative morbidity among participants receiving ketorolac will be assessed.	Prior to Hospital Discharge (generally up to 7 days post surgery)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Interleukin-1 alpha (IL-1alpha) Levels	IL-1alpha levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Interleukin-1beta (IL-1β) Levels	IL-1beta levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Interleukin-2 (IL-2) Levels	IL-2 levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Interleukin-6 (IL-6) Levels	IL-6 levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Interleukin-8 (IL-8) Levels	IL-8 levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Interleukin-10 (IL-10) Levels	IL-10 levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Interleukin-12p70 (IL-12p70) Levels	IL-12p70 levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Tumor Necrosis Factor-alpha (TNF-alpha) Levels	TNF-alpha levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Interferon (INF)-gamma Levels	INF-gamma levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Levels	GM-CSF levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Monocyte Chemotactic and Activating Factor (MCAF) Levels	MCAF levels will be compared between study arms.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Transcriptome Analysis	Transcriptome analysis will be performed to evaluate the effects of ketorolac on immune response pathways.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Flow Cytometry	Flow Cytometry will be performed to evaluate the effects of ketorolac on immune response pathways.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in T-Cell Receptor (TCR) Sequencing	T-Cell receptor (TCR) sequencing will be performed to evaluate the effects of ketorolac on immune response pathways.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28
Change in Single Cell RNA Sequencing	Single cell RNA sequencing will be performed to evaluate the effects of ketorolac on immune response pathways.	Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28

Collaborators and Investigators

• Sponsor: Emory University
• Investigators: Principal Investigator: Viraj Master, MD, PhD, Emory University; Principal Investigator: Onkar Khullar, MD, Emory University

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2020
• Primary Completion (Estimated): October 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: July 29, 2020
• First Submitted That Met QC Criteria: July 29, 2020
• First Posted (Actual): August 3, 2020

Study Record Updates

• Last Update Posted (Actual): October 24, 2023
• Last Update Submitted That Met QC Criteria: October 23, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Surgery
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ketorolac
• Other Study ID Numbers: STUDY00000205

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data which will be available for sharing includes renal function data, complications of surgery, and immune correlates.
• IPD Sharing Time Frame: Data will be available for sharing once results from this study are published.
• IPD Sharing Access Criteria: Data will be available for validation analyses.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No