Clinical trial NCT02470299: 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
Overall status: COMPLETED
Phase: NA
Conditions: Ovarian Cancer
Fallopian Tube Cancer
Peritoneal Cancer
Keywords: ketorolac
GTPase
cancer
peritoneal
fallopian
ovarian
Lead sponsor: New Mexico Cancer Research Alliance
Sponsor class: OTHER
First posted: 2015-06-12
Enrollment: 21
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Ketorolac inhibition of GTPase activity
timeFrame: Within 4 weeks of peritoneal cell collection
Secondary outcomes:
measure: Intraperitoneal and serum pharmacokinetics of ketorolac
timeFrame: Within 4 weeks of peritoneal and blood specimen collection
measure: Time to CA-125 normalization
timeFrame: Up to 6 months following first ketorolac treatment
measure: Toxicity assessment
timeFrame: Up to 30 days following first ketorolac treatment
Other outcomes:
measure: Overall survival (Exploratory objective)
timeFrame: Up to 5 years following first ketorolac treatment
measure: Progression free survival (Exploratory objective)
timeFrame: Up to 18 months following first ketorolac treatment
Locations:
city: Albuquerque
country: United States
facility: Universtiy of New Mexico Comprehensive Cancer Center
state: New Mexico
Study officials:
affiliation: University of New Mexico Comprehensive Cancer Center
name: Carolyn Y. Muller, MD
role: PRINCIPAL_INVESTIGATOR
References: