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

Sponsor
Emory University (Other)
Overall Status
Recruiting
CT.gov ID
NCT04495894
Collaborator
(none)
76
4
2
23.2
19
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Study Details

Study Description

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. 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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Preoperative Ketorolac
Early Phase 1

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 Design

Study Type:
Interventional
Anticipated Enrollment :
76 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official 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
Actual Study Start Date :
Aug 24, 2020
Anticipated Primary Completion Date :
Aug 1, 2022
Anticipated Study Completion Date :
Aug 1, 2022

Arms and Interventions

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.

    Outcome Measures

    Primary Outcome Measures

    1. Incidence of Blood Transfusion Among Ketorolac Group [Prior to Hospital Discharge (generally up to 7 days post surgery)]

      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.

    2. Incidence of Clinically Significant Hematoma Development Among Ketorolac Group [Prior to Hospital Discharge (generally up to 7 days post surgery)]

      Significant hematoma development will be assessed among participants receiving ketorolac.

    3. Incidence of Return to the Operating Room for Bleeding Among Ketorolac Group [Prior to Hospital Discharge (generally up to 7 days post surgery)]

      The need for returning to the operating room for bleeding, as determined by the treating surgeon, will be assessed among participants receiving ketorolac.

    4. Incidence of Postoperative Renal Failure Among Ketorolac Group [Prior to Hospital Discharge (generally up to 7 days post surgery)]

      Postoperative renal failure among participants receiving ketorolac will be assessed.

    5. Incidence of Postoperative Morbidity Rate Among Ketorolac Group [Prior to Hospital Discharge (generally up to 7 days post surgery)]

      Postoperative morbidity among participants receiving ketorolac will be assessed.

    Secondary Outcome Measures

    1. Change in Interleukin-1 alpha (IL-1alpha) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      IL-1alpha levels will be compared between study arms.

    2. Change in Interleukin-1beta (IL-1β) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      IL-1beta levels will be compared between study arms.

    3. Change in Interleukin-2 (IL-2) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      IL-2 levels will be compared between study arms.

    4. Change in Interleukin-6 (IL-6) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      IL-6 levels will be compared between study arms.

    5. Change in Interleukin-8 (IL-8) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      IL-8 levels will be compared between study arms.

    6. Change in Interleukin-10 (IL-10) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      IL-10 levels will be compared between study arms.

    7. Change in Interleukin-12p70 (IL-12p70) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      IL-12p70 levels will be compared between study arms.

    8. Change in Tumor Necrosis Factor-alpha (TNF-alpha) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      TNF-alpha levels will be compared between study arms.

    9. Change in Interferon (INF)-gamma Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      INF-gamma levels will be compared between study arms.

    10. Change in Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      GM-CSF levels will be compared between study arms.

    11. Change in Monocyte Chemotactic and Activating Factor (MCAF) Levels [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      MCAF levels will be compared between study arms.

    Other Outcome Measures

    1. Change in Transcriptome Analysis [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      Transcriptome analysis will be performed to evaluate the effects of ketorolac on immune response pathways.

    2. Change in Flow Cytometry [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      Flow Cytometry will be performed to evaluate the effects of ketorolac on immune response pathways.

    3. Change in T-Cell Receptor (TCR) Sequencing [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      T-Cell receptor (TCR) sequencing will be performed to evaluate the effects of ketorolac on immune response pathways.

    4. Change in Single Cell RNA Sequencing [Baseline, Day 1, Day 3 (if admitted to hospital), Day 7, Day 28]

      Single cell RNA sequencing will be performed to evaluate the effects of ketorolac on immune response pathways.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 80 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Emory University Hospital Midtown Atlanta Georgia United States 30308
    2 Emory Clinic Atlanta Georgia United States 30322
    3 Emory University Hospital Atlanta Georgia United States 30322
    4 Winship Cancer Institute Atlanta Georgia United States 30322

    Sponsors and Collaborators

    • Emory University

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Viraj Master, Professor, Emory University
    ClinicalTrials.gov Identifier:
    NCT04495894
    Other Study ID Numbers:
    • STUDY00000205
    First Posted:
    Aug 3, 2020
    Last Update Posted:
    Sep 17, 2021
    Last Verified:
    Sep 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Viraj Master, Professor, Emory University
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Sep 17, 2021