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

NCT02052908 | Completed Phase 1 DMC

• 11 other identifiers: NCI-2014-00046N01-CN-2012-00034HHSN261201200034IHUM00079757HHSN26100003; RFP BMDACC IRB # 2013-06982013-069813-585MDA2013-01-02N01CN00034P30CA016672
• Study Type: interventional
• Target: 81
• Locations: 1 country
• Sites: 4

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.

Conditions

Lynch Syndrome

Outcome Measures

Primary Outcomes (3)

• Change in PGE2 concentration levels in normal colorectal mucosa

  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.

  Baseline to 6 months

• Minimal biologically effective dose of naproxen that induces a modulation of PGE2 levels

  Up to 6 months

• Incidence of toxicity

  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.

  Up to 6 months

Secondary Outcomes (11)

• Naproxen concentrations in plasma samples

  6 months

• Naproxen concentrations in normal colorectal mucosa

  6 months

• PGE-M levels in urine samples

  6 months

• Change in number of polyps observed in the rectosigmoid area

  Baseline to 6 months

• Changes in the microRNA profile of the normal colorectal mucosa

  Baseline to 6 months

Study Arms (3)

Arm I (high-dose naproxen)

EXPERIMENTAL

Patients receive high-dose naproxen PO QD for 6 months.

Other: Laboratory Biomarker Analysis; Drug: Naproxen

Arm II (low-dose naproxen, placebo)

EXPERIMENTAL

Patients receive low-dose naproxen PO QD and placebo PO QD for 6 months.

Other: Laboratory Biomarker Analysis; Drug: Naproxen; Other: Placebo Administration

Arm III (placebo)

PLACEBO COMPARATOR

Patients receive placebo PO QD for 6 months.

Other: Laboratory Biomarker Analysis; Other: Placebo Administration

Interventions

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm I (high-dose naproxen); Arm II (low-dose naproxen, placebo); Arm III (placebo)

Naproxen DRUG

Given PO

Also known as: Naprosyn, RS-3540

Arm I (high-dose naproxen); Arm II (low-dose naproxen, placebo)

Placebo Administration OTHER

Given PO

Arm II (low-dose naproxen, placebo); Arm III (placebo)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• Reyes-Uribe L, Wu W, Gelincik O, Bommi PV, Francisco-Cruz A, Solis LM, Lynch PM, Lim R, Stoffel EM, Kanth P, Samadder NJ, Mork ME, Taggart MW, Milne GL, Marnett LJ, Vornik L, Liu DD, Revuelta M, Chang K, You YN, Kopelovich L, Wistuba II, Lee JJ, Sei S, Shoemaker RH, Szabo E, Richmond E, Umar A, Perloff M, Brown PH, Lipkin SM, Vilar E. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa. Gut. 2021 Mar;70(3):555-566. doi: 10.1136/gutjnl-2020-320946. Epub 2020 Jul 8.

  PMID: 32641470 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms, Hereditary Nonpolyposis

Interventions

Naproxen

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Neoplastic Syndromes, Hereditary; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Naphthaleneacetic Acids; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Eduardo Vilar-Sanchez

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 30, 2014
• First Posted: February 3, 2014
• Study Start: January 27, 2014
• Primary Completion: October 25, 2019
• Study Completion: January 5, 2021
• Last Updated: January 25, 2021

Record last verified: 2021-01

Locations

US (4)