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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02470299
Recruitment Status : Active, not recruiting
First Posted : June 12, 2015
Last Update Posted : December 21, 2018
Sponsor:
Information provided by (Responsible Party):
New Mexico Cancer Care Alliance

Tracking Information
First Submitted Date  ICMJE June 10, 2015
First Posted Date  ICMJE June 12, 2015
Last Update Posted Date December 21, 2018
Study Start Date  ICMJE October 2015
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2015)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02470299 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 23, 2015)
  • 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)
  • 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
  • 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2015)
  • 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)
  • Time to CA-125 normalization [ Time Frame: Up to 6 months following first ketorolac treatment ]
    CAT-125 will be measured using a standard laboratory assay
  • 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)
Current Other Pre-specified Outcome Measures
 (submitted: June 11, 2015)
  • Overall survival (Exploratory objective) [ Time Frame: Up to 5 years following first ketorolac treatment ]
    Time from treatment to death due to any cause
  • 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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Evaluation of GTPase Inhibition by Post-operative Intravenous Ketorolac in Ovarian Cancer Patients
Official Title  ICMJE A Randomized Placebo-controlled Evaluation of GTPase Inhibition by Post-operative Intravenous Ketorolac in Ovarian Cancer Patients
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE
  • Ovarian Cancer
  • Fallopian Tube Cancer
  • Peritoneal Cancer
Intervention  ICMJE
  • 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
  • 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

Study Arms  ICMJE
  • 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
    Intervention: Drug: Ketorolac
  • Placebo Comparator: Placebo
    Once deemed stable in the first 1-3 post-operative days, patients will be receive placebo daily for three days
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 19, 2018)
21
Original Estimated Enrollment  ICMJE
 (submitted: June 11, 2015)
20
Estimated Study Completion Date  ICMJE August 2021
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02470299
Other Study ID Numbers  ICMJE INST 1420
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party New Mexico Cancer Care Alliance
Study Sponsor  ICMJE New Mexico Cancer Care Alliance
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Carolyn Y. Muller, MD University of New Mexico Comprehensive Cancer Center
PRS Account New Mexico Cancer Care Alliance
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP