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

New Mexico Cancer Research Alliance

Status

Completed

Conditions

Peritoneal Cancer

Fallopian Tube Cancer

Ovarian Cancer

Treatments

Other: Placebo

Drug: Ketorolac

Study type

Interventional

Funder types

Other

Identifiers

NCT02470299

INST 1420

Details and patient eligibility

About

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.

Full 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.

Enrollment

21 patients

Sex

Female

Ages

18+ years old

Volunteers

No 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