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

Sponsor

New Mexico Cancer Care Alliance (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02470299

Collaborator

(none)

Enrollment

Location

Arms

119.3

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer	Drug: Ketorolac Other: Placebo	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

21 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Oct 29, 2015

Anticipated Primary Completion Date :

Mar 31, 2023

Anticipated Study Completion Date :

Oct 8, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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	Drug: 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 Other Names: Toradol
Placebo Comparator: Placebo Once deemed stable in the first 1-3 post-operative days, patients will be receive placebo daily for three days	Other: 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

Arm

Intervention/Treatment

Experimental: 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

Drug: 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

Other Names:

Toradol

Placebo Comparator: Placebo

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

Other: 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

Outcome Measures

Primary Outcome Measures

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

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)
Time to CA-125 normalization [Up to 6 months following first ketorolac treatment]
CA-125 will be measured using a standard laboratory assay
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)

Other Outcome Measures

Overall survival (Exploratory objective) [Up to 5 years following first ketorolac treatment]
Time from treatment to death due to any cause
Progression free survival (Exploratory objective) [Up to 18 months following first ketorolac treatment]
Time from treatment to progressive disease or death due to any cause

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts 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