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

NCT ID: NCT02470299

Last Updated: 2025-05-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-29
• Study Completion Date: 2024-01-25

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.

Conditions

Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

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

Group Type: EXPERIMENTAL

Ketorolac

Intervention Type: DRUG

Ketorolac tromethine 15 mg or 30 mg doses will be administered via intravenous (IV) push undiluted over 15 - 30 seconds

Ketorolac will be dosed according to FDA approved recommendations. For planned three daily dose (IV) based on clinical scenario:

• Patients < 65 years of age: Daily dose of 30 mg for three doses.
• Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: Daily dose of 15 mg for three doses

Blood and peritoneal fluid will be drawn prior to each dose (time 0, 24, 48, 72 hr) as well as at 6 hr after the first dose

Placebo

Once deemed stable in the first 1-3 post-operative days, patients will be receive placebo daily for three days

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Equivalent volume of normal saline will be set in the syringe for each daily dose registered for the patient in a blinded fashion. The volume will be determined by the dose calculation as follows: For planned three daily dose (IV) based on clinical scenario:

• Patients < 65 years of age: Daily dose of 30 mg for three doses.
• Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: Daily dose of 15 mg for three doses.

Blood and peritoneal fluid will be drawn prior to each dose (time 0, 24, 48, 72 hr) as well as at 6 hr after the first dose

Interventions

Ketorolac

Ketorolac tromethine 15 mg or 30 mg doses will be administered via intravenous (IV) push undiluted over 15 - 30 seconds

Ketorolac will be dosed according to FDA approved recommendations. For planned three daily dose (IV) based on clinical scenario:

• Patients < 65 years of age: Daily dose of 30 mg for three doses.
• Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: Daily dose of 15 mg for three doses

Blood and peritoneal fluid will be drawn prior to each dose (time 0, 24, 48, 72 hr) as well as at 6 hr after the first dose

Intervention Type: DRUG

Placebo

Equivalent volume of normal saline will be set in the syringe for each daily dose registered for the patient in a blinded fashion. The volume will be determined by the dose calculation as follows: For planned three daily dose (IV) based on clinical scenario:

• Patients < 65 years of age: Daily dose of 30 mg for three doses.
• Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: Daily dose of 15 mg for three doses.

Blood and peritoneal fluid will be drawn prior to each dose (time 0, 24, 48, 72 hr) as well as at 6 hr after the first dose

Intervention Type: OTHER

Other Intervention Names

Toradol

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

New Mexico Cancer Research Alliance

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carolyn Y. Muller, MD

Role: PRINCIPAL_INVESTIGATOR

University of New Mexico Comprehensive Cancer Center

Locations

Universtiy of New Mexico Comprehensive Cancer Center

Albuquerque, New Mexico, United States

Countries

United States

Other Identifiers

INST 1420

Identifier Type: -

Identifier Source: org_study_id