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

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ClinicalTrials.gov Identifier: NCT02470299
Recruitment Status : Recruiting
First Posted : June 12, 2015
Last Update Posted : August 21, 2018
Sponsor:
Information provided by (Responsible Party):
New Mexico Cancer Care Alliance

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 Not Applicable

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 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
Study Start Date : October 2015
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : August 2021


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 Name: 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





Primary Outcome Measures :
  1. Ketorolac inhibition of GTPase activity [ Time Frame: 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 :
  1. Intraperitoneal and serum pharmacokinetics of ketorolac [ Time Frame: 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)

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

  3. Toxicity assessment [ Time Frame: 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:
  1. Overall survival (Exploratory objective) [ Time Frame: Up to 5 years following first ketorolac treatment ]
    Time from treatment to death due to any cause

  2. Progression free survival (Exploratory objective) [ Time Frame: Up to 18 months following first ketorolac treatment ]
    Time from treatment to progressive disease or death due to any cause



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02470299


Contacts
Contact: Valerie Parks, RN OCN, CCRP 505-925-0390 vparks@salud.unm.edu

Locations
United States, New Mexico
Universtiy of New Mexico Comprehensive Cancer Center Recruiting
Albuquerque, New Mexico, United States, 87131-0001
Contact: Valerie Parks, BSN    505-272-0898    vparks@salud.unm.edu   
Principal Investigator: Carolyn Y. Muller, M.D.         
Sub-Investigator: Teresa Rutledge, M.D.         
Sub-Investigator: Sarah Adams, M.D.         
Sub-Investigator: Laurie Hudson, Ph.D.         
Sub-Investigator: Angela Wandinger-Ness, Ph.D.         
Sub-Investigator: Ji-Hyun Lee, Ph.D.         
Sponsors and Collaborators
New Mexico Cancer Care Alliance
Investigators
Principal Investigator: Carolyn Y. Muller, MD University of New Mexico Comprehensive Cancer Center

Responsible Party: New Mexico Cancer Care Alliance
ClinicalTrials.gov Identifier: NCT02470299     History of Changes
Other Study ID Numbers: INST 1420
First Posted: June 12, 2015    Key Record Dates
Last Update Posted: August 21, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by New Mexico Cancer Care Alliance:
ketorolac
GTPase
cancer
peritoneal
fallopian
ovarian

Additional relevant MeSH terms:
Ketorolac
Ketorolac Tromethamine
Ovarian Neoplasms
Neoplasms, Glandular and Epithelial
Fallopian Tube Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neoplasms by Histologic Type
Fallopian Tube Diseases
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action