Browse EPPT > MDA2013-01-02
Phase Ib Biomarker Trial of Naproxen in patients at risk for DNA Mismatch Repair Deficient Colorectal Cancer

The following datasets contain the data available for EPPT MDA2013-01-02. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Files	Description
Data Dictionary (PDF - 1.3 MB)	1. The Enhanced Person dataset contains all information relevant for most analyses. Each record represents one participant and contains updated variable names, formats, and labels. All information coming from non-person-based datasets has been converted into a person-based format.
Data Dictionary (PDF - 181.2 KB)	2. The Adverse Events dataset includes updated variable names, formats, and labels.

Raw Datasets

These 45 datasets contain the raw form data received, excluding PII.

Show these datasets

Files	Description
Data Dictionary (PDF - 196.5 KB)	1. The adverseevents dataset contains adverse events information
Data Dictionary (PDF - 180.4 KB)	2. The aeandconmedevaluation dataset contains adverse events and concomitant evaluation information
Data Dictionary (PDF - 182.2 KB)	3. The agentinterruption dataset contains agent interruption information
Data Dictionary (PDF - 182.7 KB)	4. The basemedsurghist dataset contains baseline medical/surgical history information
Data Dictionary (PDF - 175.6 KB)	5. The basemedsurghistother dataset contains other baseline medical/surgical history information
Data Dictionary (PDF - 177.7 KB)	6. The basesymptoms dataset contains baseline symptoms information
Data Dictionary (PDF - 185.2 KB)	7. The clinicallabdatabloodchemistry dataset contains clinical laboratory data blood chemistry information
Data Dictionary (PDF - 184.4 KB)	8. The clinicallabdatabloodchemistrygfr dataset contains clinical laboratory data blood chemistry (GFR) information
Data Dictionary (PDF - 185.2 KB)	9. The clinicallabdatahematology dataset contains clinical laboratory data hematology information
Data Dictionary (PDF - 185.7 KB)	10. The clinicallabdatahematologydiff dataset contains clinical laboratory data hematology differential information
Data Dictionary (PDF - 182.7 KB)	11. The clinicallabdataotherlabtests dataset contains clinical laboratory data other lab tests information
Data Dictionary (PDF - 200.5 KB)	12. The compliance dataset contains compliance information
Data Dictionary (PDF - 177.7 KB)	13. The compliancedruglabels dataset contains compliance drug label information
Data Dictionary (PDF - 196.1 KB)	14. The compliancephoneinterview dataset contains compliance phone interview information
Data Dictionary (PDF - 184.4 KB)	15. The concomitantmedications dataset contains concomitant medications information
Data Dictionary (PDF - 172.9 KB)	16. The eligibilityverification dataset contains eligibility verification information
Data Dictionary (PDF - 173.6 KB)	17. The exclusioncriteriav4a1 dataset contains exclusion criteria information (v4a1)
Data Dictionary (PDF - 173.9 KB)	18. The exclusioncriteriav5a2 dataset contains exclusion criteria information (v5a2)
Data Dictionary (PDF - 173.7 KB)	19. The inclusioncriteriav4a1 dataset contains inclusion criteria information (v4a1)
Data Dictionary (PDF - 174.0 KB)	20. The inclusioncriteriav5a2 dataset contains inclusion criteria information (v5a2)
Data Dictionary (PDF - 179.4 KB)	21. The interventionadminblindedstudy dataset contains intervention administration information (blinded study)
Data Dictionary (PDF - 182.7 KB)	22. The offstudy dataset contains offstudy information
Data Dictionary (PDF - 202.6 KB)	23. The outcomeofpregnancy dataset contains outcome of pregnancy information
Data Dictionary (PDF - 209.9 KB)	24. The physicalexam dataset contains physical exam information
Data Dictionary (PDF - 181.1 KB)	25. The pregnancyspecimendata dataset contains pregnancy specimen data information
Data Dictionary (PDF - 185.6 KB)	26. The randomization dataset contains randomization information
Data Dictionary (PDF - 173.1 KB)	27. The randomizationadditionalinfo dataset contains randomization additional information
Data Dictionary (PDF - 191.2 KB)	28. The registrationpart2 dataset contains registration information
Data Dictionary (PDF - 172.5 KB)	29. The registrationpart2race dataset contains registration information (race data)
Data Dictionary (PDF - 200.0 KB)	30. The specacqblooddnaextract dataset contains specimen acquisition research blood - dna extraction information
Data Dictionary (PDF - 195.4 KB)	31. The specacqbloodnaproxenlevels dataset contains specimen acquisition research blood - naproxen levels information
Data Dictionary (PDF - 201.8 KB)	32. The specacqtissuebiopsydnagenomics dataset contains specimen acquisition tissue - biopsy (dna for genomics) information
Data Dictionary (PDF - 179.5 KB)	33. The specacqtissuebiopsyhistology dataset contains biopsy tissue histology information
Data Dictionary (PDF - 199.1 KB)	34. The specacqtissuebiopsymicrorna dataset contains specimen acquisition tissue - biopsy for microrna information
Data Dictionary (PDF - 202.5 KB)	35. The specacqtissuebiopsymrnagenomics dataset contains specimen acquisition tissue - biopsy (mrna for genomics) information
Data Dictionary (PDF - 199.3 KB)	36. The specacqtissuebiopsynaproxenlevel dataset contains specimen acquisition tissue - biopsy for naproxen levels information
Data Dictionary (PDF - 199.4 KB)	37. The specacqtissuebiopsypge2levels dataset contains specimen acquisition tissue - biopsy for pge2 levels information
Data Dictionary (PDF - 198.9 KB)	38. The specacqtissuebiopsyvisit1 dataset contains specimen acquisition tissue - biopsy for biorepository (visit 1) information
Data Dictionary (PDF - 199.2 KB)	39. The specacqtissuebiopsyvisits1and6 dataset contains specimen acquisition tissue - biopsy for biorepository (visit 1 and visit 6) information
Data Dictionary (PDF - 211.6 KB)	40. The specacqtissuemucosapolypoid dataset contains biopsy tissue histology - mucosa/polypoid lesions information
Data Dictionary (PDF - 200.5 KB)	41. The specacqurinepgemlevelsvisit1 dataset contains specimen acquisition research urine - pgem levels (visit 1) information
Data Dictionary (PDF - 200.3 KB)	42. The specacqurinepgemlevelsvisit6 dataset contains specimen acquisition research urine - pgem levels (visit 6) information
Data Dictionary (PDF - 177.9 KB)	43. The telephonecontact dataset contains telephone contact information
Data Dictionary (PDF - 178.0 KB)	44. The unblindingform dataset contains unblinding information
Data Dictionary (PDF - 173.7 KB)	45. The verification dataset contains verification information

Trial Summary

This randomized phase Ib trial studies the side effects 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.

Patients are randomized to 1 of 3 treatment arms.

• ARM I: Patients receive high-dose naproxen (440 mg) orally (PO) once daily (QD) for 6 months.
• ARM II: Patients receive low-dose naproxen (220 mg) PO QD and placebo PO QD for 6 months.
• ARM III: Patients receive placebo PO QD for 6 months.

After completion of study treatment, patients are followed up for 2 weeks.

Target Randomizable Enrollment: 80

Target Evaluable Enrollment: 45

Enrollment Statistics

Actual Registration: 86

• 80 people randomized
  • 25 in Arm I: Naproxen 220 mg
  • 27 in Arm II: Naproxen 440 mg
  • 28 in Arm III: Placebo
• Six participants were not randomized; 5 participants did not meet all the screening requirements and 1 participant dropped due to target enrollment criteria limit met. (6 of 86 registered)

Eligibility 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

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Study Schema

Results/Findings:

Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control.