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

Primary Purpose

Ovarian Cancer, Fallopian Tube Cancer, Peritoneal Cancer

Status

Active

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Ketorolac

Placebo

About this trial

This is an interventional basic science trial for Ovarian Cancer focused on measuring ketorolac, GTPase, cancer, peritoneal, fallopian, ovarian

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

Universtiy of New Mexico Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Ketorolac

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Ketorolac inhibition of GTPase activity

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

Intraperitoneal and serum pharmacokinetics of ketorolac

Serum and intraperitoneal concentrations of ketorolac will be assessed over time using high performance liquid chromatography (HPLC)

Time to CA-125 normalization

CA-125 will be measured using a standard laboratory assay

Toxicity assessment

Subjective/objective evidence of developing drug toxicity will be evaluated according to NCI-CTC toxicity criteria (CTCAE version 3.0)

Full Information

NCT ID

NCT02470299

First Posted

June 10, 2015

Last Updated

October 4, 2022

Sponsor

New Mexico Cancer Care Alliance

1. Study Identification

Unique Protocol Identification Number

NCT02470299

Brief Title

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

Official Title

A Randomized Placebo-controlled Evaluation of GTPase Inhibition by Post-operative Intravenous Ketorolac in Ovarian Cancer Patients

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

October 29, 2015 (Actual)

Primary Completion Date

March 31, 2023 (Anticipated)

Study Completion Date

October 8, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

New Mexico Cancer Care Alliance

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ovarian Cancer, Fallopian Tube Cancer, Peritoneal Cancer

Keywords

ketorolac, GTPase, cancer, peritoneal, fallopian, ovarian

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantOutcomes Assessor

Allocation

Randomized

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ketorolac

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Ketorolac

Other Intervention Name(s)

Toradol

Intervention Description

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

Other

Intervention Name(s)

Placebo

Intervention Description

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

Primary Outcome Measure Information:

Title

Ketorolac inhibition of GTPase activity

Description

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

Time Frame

Within 4 weeks of peritoneal cell collection

Secondary Outcome Measure Information:

Title

Intraperitoneal and serum pharmacokinetics of ketorolac

Description

Serum and intraperitoneal concentrations of ketorolac will be assessed over time using high performance liquid chromatography (HPLC)

Time Frame

Within 4 weeks of peritoneal and blood specimen collection

Title

Time to CA-125 normalization

Description

CA-125 will be measured using a standard laboratory assay

Time Frame

Up to 6 months following first ketorolac treatment

Title

Toxicity assessment

Description

Subjective/objective evidence of developing drug toxicity will be evaluated according to NCI-CTC toxicity criteria (CTCAE version 3.0)

Time Frame

Up to 30 days following first ketorolac treatment

Other Pre-specified Outcome Measures:

Title

Overall survival (Exploratory objective)

Description

Time from treatment to death due to any cause

Time Frame

Up to 5 years following first ketorolac treatment

Title

Progression free survival (Exploratory objective)

Description

Time from treatment to progressive disease or death due to any cause

Time Frame

Up to 18 months following first ketorolac treatment

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Carolyn Y. Muller, MD

Organizational Affiliation

University of New Mexico Comprehensive Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Universtiy of New Mexico Comprehensive Cancer Center

City

Albuquerque

State/Province

New Mexico

ZIP/Postal Code

87131-0001

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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

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