Lynch SyndromePhase 1NCT02052908
Naproxen in Preventing DNA Mismatch Repair Deficient Colorectal Cancer in Patients With Lynch Syndrome
A Phase 1 study testing Laboratory Biomarker Analysis and Naproxen in people with Lynch Syndrome, run by National Cancer Institute (NCI) at 4 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Lynch Syndrome
- What is being tested?
- Laboratory Biomarker Analysis and Naproxen
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 81 participants
- Where
- 4 sitesUnited States
- Study dates
- 27 Jan 2014to 5 Jan 2021
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
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- 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
Who cannot join
- 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:
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- 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
Trial locations and contacts
4 sites in 1 country.
United States4 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
Brigham and Women's Hospital
Boston, Massachusetts, 02115
M D Anderson Cancer Center
Houston, Texas, 77030
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112
About this study
Official title: A Phase Ib Biomarker Trial of Naproxen in Patients at Risk for DNA Mismatch Repair Deficient Colorectal Cancer
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.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine whether treatment with naproxen at a once-daily 220 mg or 440-mg dose, administered for 6 months as compared to placebo reduces the concentration of prostaglandin E2 (PGE2) levels in normal colorectal mucosa in subjects at risk for a mismatch repair deficient colorectal cancer.
II. To determine the toxicity profile and tolerability of naproxen at two doses (220 mg or 440-mg once daily) as compared to placebo over 6 months of therapy in subjects at risk for a mismatch repair deficient colorectal cancer.
SECONDARY OBJECTIVES:
- To determine naproxen concentrations in plasma of patients at risk for DNA mismatch repair deficient colorectal cancer taking naproxen once daily, 220 mg, 440 mg or placebo after 6 months of therapy compared to baseline levels.
II. To determine naproxen concentrations in normal colorectal mucosa of patients at risk for DNA mismatch repair deficient colorectal cancers (CRC) taking naproxen once daily 220 mg, 440 mg or placebo after 6 months of therapy compared to baseline levels.
III. To determine whether urinary prostaglandin-endoperoxide synthase 1 metabolite (PGE-M) is significantly higher in patients at risk for DNA mismatch repair deficient CRC taking naproxen one daily, 220 mg, 440 mg or placebo after 6 months of therapy compared to baseline levels.
IV. To determine whether 6-months therapy with naproxen once daily, 220 mg, 440 mg or placebo leads to a reduction in the number of polyps observed in the rectosigmoid and rectal area.
- To determine whether naproxen once daily, 220 mg, 440 mg or placebo will significantly change the micro-ribonucleic (RNA) profile of normal colorectal mucosa in patients at risk for DNA mismatch repair deficient CRC compared to the baseline.
VI. To determine whether naproxen once daily, 220 mg, 440 mg or placebo will significantly change the gene expression messenger RNA (mRNA) profile of normal colorectal mucosa in patients at risk for DNA mismatch repair deficient CRC compared to the baseline.
VII. To determine whether naproxen once daily, 220 mg, 440 mg or placebo will significantly change the mutational rate in patients at risk for DNA mismatch repair deficient CRC compared to placebo.
VIII. To determine future candidate biomarkers measured by genomic and transcriptomic platforms in tissue biopsies of normal colorectal mucosa in individuals at risk for mismatch repair deficient CRC pre- and post-treatment with naproxen.
IX. To determine whether Naproxen once daily, 220 mg, 440 mg or placebo will significantly change the microbiome profile of normal colorectal mucosa in patients at risk for DNA mismatch repair deficient CRC compared to the baseline.
- To determine whether treatment with Naproxen once daily, 220 mg, 440 mg after 6 months of therapy as compared to placebo changed PGF2, PGD2, Thromboxane B2, 9a11b-PGF2a and 6-KetoPGF1a levels in colorectal mucosa of subjects at risk for a mismatch repair deficient colorectal cancer.
XI. To determine whether treatment with Naproxen once daily, 220 mg, 440 mg after 6 months of therapy as compared to placebo changed the number of stem cells and induced differentiation into other cell lineages in colorectal mucosa of subjects at risk for mismatch repair deficient colorectal cancer.
XII. To determine whether treatment with naproxen once daily, 220 mg, 440 mg after 6 months of therapy as compared to placebo changed the number of immune and mesenchymal cells recruited to the colorectal mucosa of subjects at risk for mismatch repair deficient colorectal cancer.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM I: Patients receive high-dose naproxen orally (PO) once daily (QD) for 6 months.
ARM II: Patients receive low-dose naproxen 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.
- Conditions
- Lynch Syndrome
- Being tested
- Laboratory Biomarker Analysis, Naproxen, Placebo Administration
- Medical subject headings
- Colorectal Neoplasms, Hereditary Nonpolyposis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Laboratory Biomarker AnalysisOther
Correlative studies
NaproxenDrug
Also called Naprosyn, RS-3540
Given PO
Placebo AdministrationOther
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Arm I (high-dose naproxen) | Experimental | Patients receive high-dose naproxen PO QD for 6 months. Receives: 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. Receives: Other: Laboratory Biomarker Analysis; Drug: Naproxen; Other: Placebo Administration |
| Arm III (placebo) | Placebo comparator | Patients receive placebo PO QD for 6 months. Receives: Other: Laboratory Biomarker Analysis; Other: Placebo Administration |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to 6 months
Minimal biologically effective dose of naproxen that induces a modulation of PGE2 levels
Measured: 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.
Measured: Up to 6 months
Secondary outcomes (11)
Naproxen concentrations in plasma samples
A t-test or the Wilcoxon rank sum test will be applied for the pairwise comparison of the changes of continuous markers among groups.
Measured: 6 months
Naproxen concentrations in normal colorectal mucosa
A t-test or the Wilcoxon rank sum test will be applied for the pairwise comparison of the changes of continuous markers among groups.
Measured: 6 months
PGE-M levels in urine samples
A t-test or the Wilcoxon rank sum test will be applied for the pairwise comparison of the changes of continuous markers among groups.
Measured: 6 months
Change in number of polyps observed in the rectosigmoid area
A t-test or the Wilcoxon rank sum test will be applied for the pairwise comparison of the changes of continuous markers among groups.
Measured: Baseline to 6 months
Changes in the microRNA profile of the normal colorectal mucosa
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.
Measured: Baseline to 6 months
Changes in gene expression mRNA profiles of the normal colorectal mucosa
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.
Measured: Baseline to 6 months
Changes in the mutational rate of the normal colorectal mucosa
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.
Measured: Baseline to 6 months
Changes in the microbiome of the normal colorectal mucosa
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.
Measured: Baseline to 6 months
Changes in the PGF2, PGD2, Thromboxane B2, 9a11b-PGF2a and 6-KetoPGF1a levels of the colorectal tissue
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.
Measured: Baseline to 6 months
Changes in the stem cell and epithelial differentiation marker levels
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.
Measured: Baseline to 6 months
Changes in the number and type of immune and mesenchymal cells recruited to the colorectal mucosa
Will be assessed by using a multiplex platform based on imaging cell cytometry (IMC) in a tissue microarray (TMA).
Measured: Baseline to 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Feb 2014 (estimated)
- Study start27 Jan 2014
- Primary completion25 Oct 2019
- Study completion5 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Lynch SyndromeStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 81 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Eduardo Vilar-Sanchez, Principal investigator, M.D. Anderson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02052908
- Sponsor's protocol ID
- NCI-2014-00046
- Other IDs
- NCI-2014-00046, N01-CN-2012-00034, HHSN261201200034I, HUM00079757, HHSN26100003; RFP B, MDACC IRB # 2013-0698, 2013-0698, 13-585
- Status last verified
- Jan 2021
- First submitted
- 30 Jan 2014
- Last updated
- 25 Jan 2021
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 32641470
Study at a glance
From the registry record, last updated by the sponsor on 25 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib Biomarker Trial of Naproxen in Patients at Risk for DNA Mismatch Repair Deficient Colorectal Cancer
- ClinicalTrials.gov ID
- NCT02052908
- Acronym / sponsor ID
- NCI-2014-00046
- Conditions
- Lynch Syndrome
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 81 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 27 Jan 2014 (actual)
- Primary completion
- 25 Oct 2019 (actual)
- Study completion
- 5 Jan 2021 (actual)
- First posted
- 3 Feb 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
PRIMARY OBJECTIVES:
- To determine whether treatment with naproxen at a once-daily 220 mg or 440-mg dose, administered for 6 months as compared to placebo reduces the concentration of prostaglandin E2 (PGE2) levels in normal colorectal mucosa in subjects at risk for a mismatch repair deficient colorectal cancer.
II. To determine the toxicity profile and tolerability of naproxen at two doses (220 mg or 440-mg once daily) as compared to placebo over 6 months of therapy in subjects at risk for a mismatch repair deficient colorectal cancer.
SECONDARY OBJECTIVES:
- To determine naproxen concentrations in plasma of patients at risk for DNA mismatch repair deficient colorectal cancer taking naproxen once daily, 220 mg, 440 mg or placebo after 6 months of therapy compared to baseline levels.
II. To determine naproxen concentrations in normal colorectal mucosa of patients at risk for DNA mismatch repair deficient colorectal cancers (CRC) taking naproxen once daily 220 mg, 440 mg or placebo after 6 months of therapy compared to baseline levels.
III. To determine whether urinary prostaglandin-endoperoxide synthase 1 metabolite (PGE-M) is significantly higher in patients at risk for DNA mismatch repair deficient CRC taking naproxen one daily, 220 mg, 440 mg or placebo after 6 months of therapy compared to baseline levels.
IV. To determine whether 6-months therapy with naproxen once daily, 220 mg, 440 mg or placebo leads to a reduction in the number of polyps observed in the rectosigmoid and rectal area.
- To determine whether naproxen once daily, 220 mg, 440 mg or placebo will significantly change the micro-ribonucleic (RNA) profile of normal colorectal mucosa in patients at risk for DNA mismatch repair deficient CRC compared to the baseline.
VI. To determine whether naproxen once daily, 220 mg, 440 mg or placebo will significantly change the gene expression messenger RNA (mRNA) profile of normal colorectal mucosa in patients at risk for DNA mismatch repair deficient CRC compared to the baseline.
VII. To determine whether naproxen once daily, 220 mg, 440 mg or placebo will significantly change the mutational rate in patients at risk for DNA mismatch repair deficient CRC compared to placebo.
VIII. To determine future candidate biomarkers measured by genomic and transcriptomic platforms in tissue biopsies of normal colorectal mucosa in individuals at risk for mismatch repair deficient CRC pre- and post-treatment with naproxen.
IX. To determine whether Naproxen once daily, 220 mg, 440 mg or placebo will significantly change the microbiome profile of normal colorectal mucosa in patients at risk for DNA mismatch repair deficient CRC compared to the baseline.
- To determine whether treatment with Naproxen once daily, 220 mg, 440 mg after 6 months of therapy as compared to placebo changed PGF2, PGD2, Thromboxane B2, 9a11b-PGF2a and 6-KetoPGF1a levels in colorectal mucosa of subjects at risk for a mismatch repair deficient colorectal cancer.
XI. To determine whether treatment with Naproxen once daily, 220 mg, 440 mg after 6 months of therapy as compared to placebo changed the number of stem cells and induced differentiation into other cell lineages in colorectal mucosa of subjects at risk for mismatch repair deficient colorectal cancer.
XII. To determine whether treatment with naproxen once daily, 220 mg, 440 mg after 6 months of therapy as compared to placebo changed the number of immune and mesenchymal cells recruited to the colorectal mucosa of subjects at risk for mismatch repair deficient colorectal cancer.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM I: Patients receive high-dose naproxen orally (PO) once daily (QD) for 6 months.
ARM II: Patients receive low-dose naproxen 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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm I (high-dose naproxen) | Experimental | Other: Laboratory Biomarker Analysis, Drug: NaproxenPatients receive high-dose naproxen PO QD for 6 months. |
| Arm II (low-dose naproxen, placebo) | Experimental | Other: Laboratory Biomarker Analysis, Drug: Naproxen, Other: Placebo AdministrationPatients receive low-dose naproxen PO QD and placebo PO QD for 6 months. |
| Arm III (placebo) | Placebo comparator | Other: Laboratory Biomarker Analysis, Other: Placebo AdministrationPatients receive placebo PO QD for 6 months. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Participants must have Lynch syndrome defined as meeting any of the following:
- 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
Key exclusion criteria (25 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Laboratory Biomarker AnalysisCorrelative studies | Other | Arm I (high-dose naproxen), Arm II (low-dose naproxen, placebo), Arm III (placebo) |
| NaproxenAlso: Naprosyn, RS-3540Given PO | Drug | Arm I (high-dose naproxen), Arm II (low-dose naproxen, placebo) |
| Placebo AdministrationGiven PO | Other | Arm II (low-dose naproxen, placebo), Arm III (placebo) |
Primary outcome
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.
Minimal biologically effective dose of naproxen that induces a modulation of PGE2 levels
Time frame: Up to 6 months
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.
11 secondary outcomes
Naproxen concentrations in plasma samples
Time frame: 6 months
Naproxen concentrations in normal colorectal mucosa
Time frame: 6 months
PGE-M levels in urine samples
Time frame: 6 months
Change in number of polyps observed in the rectosigmoid area
Time frame: Baseline to 6 months
Changes in the microRNA profile of the normal colorectal mucosa
Time frame: Baseline to 6 months
Changes in gene expression mRNA profiles of the normal colorectal mucosa
Time frame: Baseline to 6 months
Changes in the mutational rate of the normal colorectal mucosa
Time frame: Baseline to 6 months
Changes in the microbiome of the normal colorectal mucosa
Time frame: Baseline to 6 months
Changes in the PGF2, PGD2, Thromboxane B2, 9a11b-PGF2a and 6-KetoPGF1a levels of the colorectal tissue
Time frame: Baseline to 6 months
Changes in the stem cell and epithelial differentiation marker levels
Time frame: Baseline to 6 months
Changes in the number and type of immune and mesenchymal cells recruited to the colorectal mucosa
Time frame: Baseline to 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jan 2021.
- Derived from this study: PubMed 32641470Reyes-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.
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Prostate Cancer
Active, not recruitingPhase 3
Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair
Colon Adenocarcinoma, DNA Repair Disorder
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Eduardo Vilar-Sanchez principal investigator
M.D. Anderson Cancer Center
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Laboratory Biomarker Analysis and Naproxen in people with Lynch Syndrome, run by National Cancer Institute (NCI) at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in PGE2 concentration levels in normal colorectal mucosa (time frame: Baseline to 6 months). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02052908, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jan 2021.