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Naproxen in Preventing DNA Mismatch Repair Deficient Colorectal Cancer in Patients With Lynch Syndrome

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: NCT02052908
Recruitment Status : Active, not recruiting
First Posted : February 3, 2014
Last Update Posted : August 20, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase Ib trial studies the side effects and best dose of naproxen in preventing deoxyribonucleic acid (DNA) mismatch repair deficient colorectal cancer in patients with Lynch syndrome. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of naproxen may keep cancer from forming in patients with Lynch syndrome.

Condition or disease Intervention/treatment Phase
Lynch Syndrome Other: Laboratory Biomarker Analysis Drug: Naproxen Other: Placebo Administration Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 81 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: A Phase Ib Biomarker Trial of Naproxen in Patients at Risk for DNA Mismatch Repair Deficient Colorectal Cancer
Actual Study Start Date : January 27, 2014
Actual Primary Completion Date : October 25, 2017


Arm Intervention/treatment
Experimental: Arm I (high-dose naproxen)
Patients receive high-dose naproxen PO QD for 6 months.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Naproxen
Given PO
Other Names:
  • Naprosyn
  • RS-3540

Experimental: Arm II (low-dose naproxen, placebo)
Patients receive low-dose naproxen PO QD and placebo PO QD for 6 months.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Naproxen
Given PO
Other Names:
  • Naprosyn
  • RS-3540

Other: Placebo Administration
Given PO

Placebo Comparator: Arm III (placebo)
Patients receive placebo PO QD for 6 months.
Other: Laboratory Biomarker Analysis
Correlative studies

Other: Placebo Administration
Given PO




Primary Outcome Measures :
  1. Change in PGE2 concentration levels in normal colorectal mucosa [ Time Frame: Baseline to 6 months ]
    Response will be defined as >= 30% reduction in PGE2 levels. Pairwise comparisons by the two-sample t-test among the three groups (low-dose versus control, high-dose versus control, and high-dose versus low-dose) will be used. The calculation adjusts for 3 multiple comparisons using the Bonferroni correction to achieve a two-sided 5% type I error. The point estimate and the 95% exact confidence interval for the response rate will be calculated in each arm.

  2. Minimal biologically effective dose of naproxen that induces a modulation of PGE2 levels [ Time Frame: Up to 6 months ]
  3. Incidence of toxicity [ Time Frame: Up to 6 months ]
    Will be graded according to National Cancer Institute Common Criteria for Adverse Events version 4.0. Descriptive statistics will be used to monitor the type and grade of toxicities. The frequency of toxicities will be compared between the placebo and naproxen groups.


Secondary Outcome Measures :
  1. Naproxen concentrations in plasma samples [ Time Frame: 6 months ]
    A t-test or the Wilcoxon rank sum test will be applied for the pairwise comparison of the changes of continuous markers among groups.

  2. Naproxen concentrations in normal colorectal mucosa [ Time Frame: 6 months ]
    A t-test or the Wilcoxon rank sum test will be applied for the pairwise comparison of the changes of continuous markers among groups.

  3. PGE-M levels in urine samples [ Time Frame: 6 months ]
    A t-test or the Wilcoxon rank sum test will be applied for the pairwise comparison of the changes of continuous markers among groups.

  4. Change in number of polyps observed in the rectosigmoid area [ Time Frame: Baseline to 6 months ]
    A t-test or the Wilcoxon rank sum test will be applied for the pairwise comparison of the changes of continuous markers among groups.

  5. Changes in the microRNA profile of the normal colorectal mucosa [ Time Frame: Baseline to 6 months ]
    Bioinformatic methods such as the beta-uniform mixture (BUM) model to account for multiple testing by controlling the false discovery rate (FDR), the Wilcoxon rank-sum test with empirical Bayes, and the significance analysis of microarrays (SAM) with the control of the FDR will be applied using the Object-Oriented Microarray and Proteomic Analysis (OOMPA) program.

  6. Changes in gene expression mRNA profiles of the normal colorectal mucosa [ Time Frame: Baseline to 6 months ]
    Bioinformatic methods such as the BUM model to account for multiple testing by controlling the FDR, the Wilcoxon rank-sum test with empirical Bayes, and the SAM with the control of the FDR will be applied using the OOMPA program.

  7. Changes in the mutational rate of the normal colorectal mucosa [ Time Frame: Baseline to 6 months ]
    Bioinformatic methods such as the BUM model to account for multiple testing by controlling the FDR, the Wilcoxon rank-sum test with empirical Bayes, and the SAM with the control of the FDR will be applied using the OOMPA program.

  8. Changes in the microbiome of the normal colorectal mucosa [ Time Frame: Baseline to 6 months ]
    Bioinformatic methods such as the BUM model to account for multiple testing by controlling the FDR, the Wilcoxon rank-sum test with empirical Bayes, and the SAM with the control of the FDR will be applied using the OOMPA program.

  9. Changes in the PGF2, PGD2, Thromboxane B2, 9a11b-PGF2a and 6-KetoPGF1a levels of the colorectal tissue [ Time Frame: Baseline to 6 months ]
    Bioinformatic methods such as the BUM model to account for multiple testing by controlling the FDR, the Wilcoxon rank-sum test with empirical Bayes, and the SAM with the control of the FDR will be applied using the OOMPA program.

  10. Changes in the stem cell and epithelial differentiation marker levels [ Time Frame: Baseline to 6 months ]
    Bioinformatic methods such as the BUM model to account for multiple testing by controlling the FDR, the Wilcoxon rank-sum test with empirical Bayes, and the SAM with the control of the FDR will be applied using the OOMPA program.

  11. Changes in the number and type of immune and mesenchymal cells recruited to the colorectal mucosa [ Time Frame: Baseline to 6 months ]
    Will be assessed by using a multiplex platform based on imaging cell cytometry (IMC) in a tissue microarray (TMA).



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Participants must have Lynch syndrome defined as meeting any of the following:

    • "Mutation-positive Lynch syndrome": carriers or obligate carriers (by pedigree) of a pathogenic mutation in one of the DNA mismatch repair (MMR) genes (i.e. mutL homolog 1 [MLH1], mutS homolog 2 [MSH2]/epithelial cell adhesion molecule [EPCAM], mutS homolog 6 [MSH6], or PMS2 postmeiotic segregation increased 2 [S. cerevisiae] [PMS2]) or
    • "Mutation-negative Lynch syndrome": patients with a personal history of a non-sporadic MMR deficient premalignant lesion (i.e. polyp) or a non-sporadic MMR deficient malignant tumor (where "non-sporadic MMR deficient" is defined by: microsatellite-instability high by either immunohistochemistry or microsatellite instability [MSI] testing or both, but no evidence of MLH1 promoter methylation in cases with loss of both MLH1 and PMS2, and/or no evidence of v-raf murine sarcoma viral oncogene homolog B [BRAF] mutation in cases with loss of both MLH1 and PMS2) but germline MMR genetic testing showed either a variant of unknown significance or mutation negative result or had declined germline MMR genetic testing
  • Participants must not have evidence of active/recurrent malignant disease for 6 months
  • Participants must be at least 6 months from any prior cancer-directed treatment (such as surgical resection, chemotherapy, immunotherapy, hormonal therapy or radiation)
  • Participants must have endoscopically accessible distal colon and/or rectal mucosa (i.e. participants must have at least part of the descending/sigmoid colon and/or rectum intact)
  • Participants must consent to one standard of care lower gastrointestinal (GI) endoscopy (flexible sigmoidoscopy or colonoscopy) with biopsies and one flexible sigmoidoscopy with biopsies that will be 6 months (+14 days) apart
  • Participants must consent to refrain from using aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-inhibitors for the duration of the trial
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Hemoglobin >= 10 g/dL or hematocrit >= 30%
  • Leukocyte count >= 3,000/microliter
  • Platelet count >= 100,000/microliter
  • Absolute neutrophil count >= 1,500/microliter
  • Creatinine =< 1.5 x institutional upper limit of normal (ULN) (OR glomerular filtration rate [GFR] > 30 ml/min/1.73 m^2)
  • Total bilirubin =< 2 x institutional ULN
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x institutional ULN
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
  • The effects of naproxen on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because NSAIDs are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation; should a woman become pregnant or suspect she is pregnant at the time of study entry or while participating in this study, she should inform her study physician immediately; women of childbearing potential must agree to baseline and pre-drug pregnancy tests
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Individuals who received scheduled aspirin, NSAIDs, or COX-inhibitors of any kind for more than 3 days (> 3 days) during anytime within the 2 weeks preceding baseline eligibility screening visit; individuals on cardio-protective aspirin will not be eligible
  • Individuals who are status post total proctocolectomy (i.e. removal of all colon and rectum)
  • Individuals with active gastroduodenal ulcer disease in the preceding 5 years
  • Individuals with any history of transfusion-dependent gastrointestinal bleeding, gastrointestinal perforation or gastrointestinal obstruction; if any of these events had been due to a malignancy of the GI tract and the malignancy has since been removed, the patient is eligible
  • Individuals with history of myocardial infarction, stroke, coronary-artery bypass draft, invasive coronary revascularization in the preceding 5 years
  • Individuals taking the drugs listed below may not be randomized unless they are willing to stop the medications (and possibly change to alternative non-excluded medications to treat the same conditions) no less than 7 days prior to starting naproxen or placebo on this study; consultation with the participant's primary care provider may be obtained but is not required; the use of the following drugs or drug classes is prohibited during naproxen/placebo treatment:

    • Investigational agents
    • NSAIDs: such as aspirin, ketorolac and others NSAIDs
    • COX-2 inhibitors: such as celecoxib, rofecoxib and other COX-2
    • Antiplatelet agents: such as aspirin, clopidogrel, ticlopidine, dipyridamole, abciximab, tirofiban, eptifibatide and prasugrel
    • Anticoagulants:

      • Heparin
      • Heparinoids: such as fondaparinux, danaparoid and other heparinoids
      • Low-molecular weight heparins: such as enoxaparin, dalteparin, parnaparin, reviparin, tinzaparin, ardeparin, certoparin, lepirudin, bivalirudin
      • Other anticoagulants: argatroban, apixaban, dabigatran, rivaroxaban, warfarin, acenocoumarol, dicumarol, phenindione and other anticoagulants
    • Lithium
    • Selective serotonin and norepinephrine reuptake inhibitors: milnacipran, fluoxetine, paroxetine, nefazodone, citalopram, clovoxamine, escitalopram, flesinoxan, femoxetine, duloxetine, venlafaxine, vilazodone, sibutramine, desvenlafaxine
    • Anticonvulsants: phenytoin, paraldehyde, valproic acid, carbamazepine, trimethadione, phenobarbital, diazepam, chlormethiazole, mephenytoin, ethotoin, paramethadione, phenacemide, mephobarbital, oxcarbazepine, zonisamide, piracetam, vigabatrin, felbamate, gabapentin, beclamide, fosphenytoin, stiripentol, tiagabine, topiramate, pregabalin, lacosamide, rufinamide, caramiphen
    • Antibiotics and antifungals:

      • Fluoroquinolones : such as ofloxacin, norfloxacin, levofloxacin
    • Other agents: teriflunomide, cyclosporine, tacrolimus, ginkgo, gossypol, meadowsweet, feverfew, beta glucan, pentosan, pentoxifylline, cilostazol, erlotinib, pemetrexed, methotrexate, pralatrexate
  • Individuals with uncontrolled renal insufficiency or renal failure
  • History of allergic reactions attributed to naproxen
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant, breast-feeding, or women of childbearing potential unwilling to use a reliable contraceptive method; pregnant women are excluded from this study because naproxen/NSAIDs is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with naproxen, breastfeeding should be discontinued if the mother is treated with naproxen

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): NCT02052908


Locations
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United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
United States, Michigan
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Utah
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Eduardo Vilar-Sanchez M.D. Anderson Cancer Center
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02052908    
Obsolete Identifiers: NCT02048735
Other Study ID Numbers: NCI-2014-00046
NCI-2014-00046 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00034
HHSN261201200034I
HUM00079757
HHSN26100003; RFP B
MDACC IRB # 2013-0698
2013-0698
13-585
2013-0698 ( Other Identifier: M D Anderson Cancer Center )
MDA2013-01-02 ( Other Identifier: DCP )
N01CN00034 ( U.S. NIH Grant/Contract )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: February 3, 2014    Key Record Dates
Last Update Posted: August 20, 2020
Last Verified: August 2020
Additional relevant MeSH terms:
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Colorectal Neoplasms, Hereditary Nonpolyposis
Syndrome
Disease
Pathologic Processes
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Neoplastic Syndromes, Hereditary
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Naproxen
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
Gout Suppressants
Cyclooxygenase Inhibitors
Enzyme Inhibitors