Evaluation of GTPase Inhibition by Post-operative Intravenous Ketorolac in Ovarian Cancer Patients

Not Applicable

Completed

• Conditions: Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer
• Interventions: Other: Placebo; Drug: Ketorolac

• Registration Number: NCT02470299
• Lead Sponsor: New Mexico Cancer Research Alliance

Brief Summary

There is a move towards personalized medicine in cancer care, and significant effort is underway to evaluate new targeted therapeutics for the treatment of ovarian cancer. One way to identify potential new drug targets is by screening a drug library to determine whether drugs in the library target key kinase or enzymatic sites in cellular signaling pathways. Previous preclinical work and pilot studies demonstrated that ketorolac (a type of non-steroidal anti-inflammatory drug) inhibits GTPase activity in ovarian cancer cells retrieved from the post-operative peritoneal cavity.

The purpose of this study is to confirm that this inhibitory effect is ketorolac driven and not a specific effect of the post-operative peritoneal compartment.

Detailed Description

Drug repurposing, screening a library of FDA approved agents, can identify agents that are clinically available and for which pharmacology and pharmacokinetics are known and preclinical data can be generated rapidly without the subsequent need for GMP (good manufacturing practice) new drug production. Small GTPases, including members of the Rab, Ras and Rho families, are attractive targets for the development of cancer therapeutics based on their pivotal roles in protein trafficking, proliferation/survival and cytoskeletal organization, respectively. Ketorolac tromethamine is a non-steroidal anti-inflammatory drug that was identified in previous in-silico drug screens to be an inhibitor of GTPases. In a previous phase 0 clinical study, ketorolac was administered intravenously to ovarian cancer patients following optimal cytoreductive surgery. Ovarian cancer cells were obtained at the time of surgery, prior to ketorolac administration, and at various times after ketorolac dosing. Analysis of GTPase activity in these specimens showed a time-dependent inhibition of Rac1 and Cdc42 GTPase activity. The purpose of this study is to confirm that the effect is ketorolac driven and not a specific effect of the post-operative peritoneal compartment.

Study Timeline

• Study First Submitted: 2015-06-10
• Study First Submitted QC: 2015-06-11
• Study First Posted: 2015-06-12
• Study Start: 2015-10-29
• Primary Completion: 2018-10-08
• Study Completion: 2024-01-25
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-20
• Last Update Posted: 2025-05-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 21

Inclusion Criteria

• Patients must be suspected of having a diagnosis of ovarian, fallopian tube or primary peritoneal cancer with a planned cytoreductive surgery.

• Borderline ovarian cancer with ascites is allowable.

• ECOG/Zubrod/SWOG Performance Status <2 (Karnofsky Performance Status > 70%)

• Female' age ≥18 years

• Ability to provide informed consent

• Baseline laboratory values (bone marrow, renal, hepatic):

  • Adequate bone marrow function:

    • Absolute neutrophil count >1000/µL
    • Platelet count >100'000/µL

  • Renal function:

    • Serum creatinine < 1.5 x ULN

  • Hepatic function:

    • Bilirubin <1.5x normal
    • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels ≤ 2 x ULN

• No known bleeding disorders

• No known sensitivity or allergy to NSAIDs

• No active peptic ulcer disease

• No active bleeding

Secondary Eligibility

• Histologic diagnosis of epithelial ovarian, fallopian tube or primary peritoneal cancer confirmed on frozen section diagnosis during debulking surgery
• Attempted maximal cytoreductive surgery. Patients will still be eligible whether optimal or suboptimally debulked at the completion of the surgery.
• No active bleeding in the post-operative period

Exclusion Criteria

• Non-epithelial ovarian cancer or metastatic cancer from another site to the ovaries
• Borderline ovarian cancer without ascites
• Uncontrolled or unstable medical conditions
• Off study use of ketorolac or other NSAIDs prior to study administration within the perioperative window (7 days before surgery and up to the time of planned study administration)
• Active bleeding or high risk of bleeding
• Active therapeutic anticoagulation
• Known hypersensitivity to NSAIDs
• Chronic or acute renal insufficiency as defined by a preoperative serum creatinine greater than 1.5 mg/dL or creatinine clearance of < 40 ml/min
• Any co-morbid condition that' in the view of the attending physician' renders the patient at high risk from ketorolac treatment complications

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Once deemed stable in the first 1-3 post-operative days, patients will be receive placebo daily for three days
Ketorolac	Ketorolac	Once deemed stable in the first 1-3 post-operative days, patients will be receive age-based ketorolac (30 mg \<65, 15mg \> 65) daily for three days

Primary Outcome Measures

Name	Time	Method
Ketorolac inhibition of GTPase activity	Within 4 weeks of peritoneal cell collection	Ovarian cancer cells retrieved from the post-debulked peritoneal cavity after three intravenous dosings of ketorolac will be evaluated for GTPase activity using cell-based laboratory assays

Secondary Outcome Measures

Name	Time	Method
Intraperitoneal and serum pharmacokinetics of ketorolac	Within 4 weeks of peritoneal and blood specimen collection	Serum and intraperitoneal concentrations of ketorolac will be assessed over time using high performance liquid chromatography (HPLC)
Toxicity assessment	Up to 30 days following first ketorolac treatment	Subjective/objective evidence of developing drug toxicity will be evaluated according to NCI-CTC toxicity criteria (CTCAE version 3.0)
Time to CA-125 normalization	Up to 6 months following first ketorolac treatment	CA-125 will be measured using a standard laboratory assay

Trial Locations

Locations (1)

Universtiy of New Mexico Comprehensive Cancer Center; 🇺🇸 Albuquerque, New Mexico, United States