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A Phase IIa Randomized, Double-Blinded Clinical Trial of Naproxen or Aspirin for Cancer Immune Interception in Lynch Syndrome

Primary Purpose

T Cells, Colorectal Cancer, Lynch Syndrome

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Naproxen
Aspirin
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for T Cells

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

    1. "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., MLH1, MSH2/EPCAM, MSH6, or PMS2).
    2. "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 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 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 test-ing.
  • 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., partici-pants must have at least part of the descending/sigmoid colon and/or rectum intact).
  • Participants must consent to one standard of care lower GI endoscopy (flexible sigmoidoscopy or colonoscopy) with biopsies and one flexible sigmoidoscopy with biopsies that will be 12 months (+14 days) apart.
  • Participants must consent to refrain from using aspirin or NSAIDs or COX-inhibitors for the du-ration of the trial
  • Age ≥18 years. Because no dosing or adverse event data are currently available on the long-term use of naproxen or aspirin in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable.
  • ECOG performance status ≤1 OR Karnofsky ≥70%; see Appendix A.
  • Participants must have normal organ and marrow function as defined below:

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 ULN (OR GFR >30ml/min/1.73m2) Total bilirubin ≤2 x institutional ULN AST (SGOT) ≤2.5 × institutional ULN ALT (SGPT) ≤2.5 × 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 base-line and pre-drug pregnancy tests.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Willing and able to adhere to the prohibitions and restrictions specified in the final approved pro-tocol.
  • Willing to undergo yearly standard of care screening colonoscopy for the duration of the clinical trial.

Exclusion Criteria:

  • Individuals with presence of two somatic mutations/loss of heterozygosity (LOH) in one of the four MMR genes (MLH1, MSH2, MSH6, and PMS2) in MMR-deficient neoplasm (defined as a tumor with MSI-H by PCR analysis or loss of staining in one of the four MMR proteins).
  • Individuals who received scheduled NSAIDs or COX-inhibitors of any kind for >3 days during anytime within the 2 weeks prior to baseline eligibility screening visit. By exception, individuals receiving cardio-protective aspirin (e.g., 81 mg PO daily) will be eligible provided they are will-ing to stop no less than 7 days prior to starting on naproxen or aspirin in this study.
  • 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 aspirin 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/aspirin treatment:

    • Investigational agents;
    • NSAIDs: such as ketorolac, sulindac, ibuprofen, and others;
    • COX-2 inhibitors: such as Celecoxib, Rofecoxib and other COX-2;
    • Antiplatelet agents: such as aspirin, clopidogrel, ticlopidine, dipyridamole, abciximab, tirofi-ban, 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, lepidurin, bivalidurin;
      • Other anticoagulants: argatroban, apixaban, dabigatran, rivaroxaban, warfarin, aceno-coumarol, dicumarol, phenindione and other anticoagulants;
    • Lithium;
    • Selective serotonin and norepinephrine reuptake inhibitors: minalcipran, fluoxetine, paroxe-tine, nefazadine, citalopram, clovoxamine, escitalopram, flesinoxan, femoxitene, duloxetine, venlafaxine, vilazodone, sibutramine, desvenlafaxine;
    • Anticonvulsants: phenytoin, parakdehyde, valproic acid, carbamazepine, trimethadione, phenobarbital, diazepam, chlormethiazole, mephenytoin, ethotoin, paramethadione, phenac-emide, mephobarbital, oxcarbazepine, zonisamide, piracetam, vigabatrin, felbamate, gabapentin, beclamide, phosphenytoin, stripentol, tiagabine, topiramate, pregabalin, lacosa-mide, rufinamide, caramiphen;
    • Antibiotics and antifungals:

      o Fluorquinolones: such as ofloxacin, norfloxacin, levofloxacin;

    • Other agents: teriflunomide, cyclosporine, tacrolimus, ginkgo, gossypol, meadowsweet, fe-verfew, beta glucan, pentosan, pentoxifylline, cilostazol, erlotinib, pemetrexed, methotrex-ate, pralatrexate.
  • Individuals with uncontrolled renal insufficiency or renal failure.
  • History of allergic reactions attributed to naproxen or aspirin.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncon-trolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac ar-rhythmia, or psychiatric illness/social situations that would limit compliance with study require-ments.
  • Pregnant, breast-feeding, or women of childbearing potential unwilling to use a reliable contra-ceptive 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 or aspirin, breastfeeding should be discontinued if the mother is treated with naproxen.

Inclusion of Women and Minorities:

-Participants will be adult men and women of all races and ethnic groups, who are at least 18 years old, and who are deemed eligible for this trial. Children will not be recruited to the trial.

Our minority recruitment strategies will include identifying participants through the University of Texas MD Anderson Cancer Center Familial High-Risk Gastrointestinal Cancer Clinic and Weill Cornell Med-ical College. We will advertise the study on minority and other national websites.

Sites / Locations

  • MD Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Naproxen

Aspirin

Arm Description

Participants will take two (2) naproxen matching capsules by mouth 1 time every day, at about the same time each day

Participants will take two (2) aspirin matching capsules by mouth 1 time every day, at about the same time each day

Outcomes

Primary Outcome Measures

To establish the effect of naproxen or aspirin on the abundance of T cells and other immune

Secondary Outcome Measures

Full Information

First Posted
June 1, 2022
Last Updated
September 1, 2023
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Institutes of Health (NIH), National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT05411718
Brief Title
A Phase IIa Randomized, Double-Blinded Clinical Trial of Naproxen or Aspirin for Cancer Immune Interception in Lynch Syndrome
Official Title
A Phase IIa Randomized, Double-Blinded Clinical Trial of Naproxen or Aspirin for Cancer Immune Interception in Lynch Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 21, 2023 (Actual)
Primary Completion Date
November 30, 2025 (Anticipated)
Study Completion Date
November 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Institutes of Health (NIH), National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
To learn about the effects of naproxen and aspirin on the normal colon in people with Lynch Syndrome.
Detailed Description
Primary Objectives: To evaluate the effect of naproxen or aspirin on the abundance of T cells and other im-mune cell types in the normal colorectal mucosa of participants with Lynch syndrome (LS) using single-cell approaches. Secondary Objectives: To evaluate cell-type specific effects of treatment with naproxen or aspirin on gene ex-pression in the normal colorectal mucosa and endometrium in participants with LS using single-cell approaches. To evaluate the effect of treatment with naproxen or aspirin on the spatial distribution of immune-related cell types in the normal colorectal mucosa and endometrium in of partic-ipants with LS using multiplex imaging approaches. To assess the effect of treatment with naproxen or aspirin on colorectal polyp burden in participants with LS. To assess the safety profile of treatment with naproxen or aspirin in participants with LS. To assess the effect of treatment with naproxen or aspirin in normal mucosa, stool and periodontal microbiome in participants with LS. To compare the effect of naproxen or aspirin on the abundance of T cells and other im-mune cell types in the normal colorectal mucosa, endometrium and peripheral blood of participants with LS. To assess the symptoms of LS participants randomized to naproxen or aspirin.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
T Cells, Colorectal Cancer, Lynch Syndrome

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Naproxen
Arm Type
Experimental
Arm Description
Participants will take two (2) naproxen matching capsules by mouth 1 time every day, at about the same time each day
Arm Title
Aspirin
Arm Type
Active Comparator
Arm Description
Participants will take two (2) aspirin matching capsules by mouth 1 time every day, at about the same time each day
Intervention Type
Drug
Intervention Name(s)
Naproxen
Intervention Description
Given by PO
Intervention Type
Drug
Intervention Name(s)
Aspirin
Intervention Description
Given by PO
Primary Outcome Measure Information:
Title
To establish the effect of naproxen or aspirin on the abundance of T cells and other immune
Time Frame
through study completion, an average of 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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., MLH1, MSH2/EPCAM, MSH6, or PMS2). "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 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 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 test-ing. 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., partici-pants must have at least part of the descending/sigmoid colon and/or rectum intact). Participants must consent to one standard of care lower GI endoscopy (flexible sigmoidoscopy or colonoscopy) with biopsies and one flexible sigmoidoscopy with biopsies that will be 12 months (+14 days) apart. Participants must consent to refrain from using aspirin or NSAIDs or COX-inhibitors for the du-ration of the trial Age ≥18 years. Because no dosing or adverse event data are currently available on the long-term use of naproxen or aspirin in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable. ECOG performance status ≤1 OR Karnofsky ≥70%; see Appendix A. Participants must have normal organ and marrow function as defined below: 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 ULN (OR GFR >30ml/min/1.73m2) Total bilirubin ≤2 x institutional ULN AST (SGOT) ≤2.5 × institutional ULN ALT (SGPT) ≤2.5 × 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 base-line and pre-drug pregnancy tests. Ability to understand and the willingness to sign a written informed consent document. Willing and able to adhere to the prohibitions and restrictions specified in the final approved pro-tocol. Willing to undergo yearly standard of care screening colonoscopy for the duration of the clinical trial. Exclusion Criteria: Individuals with presence of two somatic mutations/loss of heterozygosity (LOH) in one of the four MMR genes (MLH1, MSH2, MSH6, and PMS2) in MMR-deficient neoplasm (defined as a tumor with MSI-H by PCR analysis or loss of staining in one of the four MMR proteins). Individuals who received scheduled NSAIDs or COX-inhibitors of any kind for >3 days during anytime within the 2 weeks prior to baseline eligibility screening visit. By exception, individuals receiving cardio-protective aspirin (e.g., 81 mg PO daily) will be eligible provided they are will-ing to stop no less than 7 days prior to starting on naproxen or aspirin in this study. 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 aspirin 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/aspirin treatment: Investigational agents; NSAIDs: such as ketorolac, sulindac, ibuprofen, and others; COX-2 inhibitors: such as Celecoxib, Rofecoxib and other COX-2; Antiplatelet agents: such as aspirin, clopidogrel, ticlopidine, dipyridamole, abciximab, tirofi-ban, 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, lepidurin, bivalidurin; Other anticoagulants: argatroban, apixaban, dabigatran, rivaroxaban, warfarin, aceno-coumarol, dicumarol, phenindione and other anticoagulants; Lithium; Selective serotonin and norepinephrine reuptake inhibitors: minalcipran, fluoxetine, paroxe-tine, nefazadine, citalopram, clovoxamine, escitalopram, flesinoxan, femoxitene, duloxetine, venlafaxine, vilazodone, sibutramine, desvenlafaxine; Anticonvulsants: phenytoin, parakdehyde, valproic acid, carbamazepine, trimethadione, phenobarbital, diazepam, chlormethiazole, mephenytoin, ethotoin, paramethadione, phenac-emide, mephobarbital, oxcarbazepine, zonisamide, piracetam, vigabatrin, felbamate, gabapentin, beclamide, phosphenytoin, stripentol, tiagabine, topiramate, pregabalin, lacosa-mide, rufinamide, caramiphen; Antibiotics and antifungals: o Fluorquinolones: such as ofloxacin, norfloxacin, levofloxacin; Other agents: teriflunomide, cyclosporine, tacrolimus, ginkgo, gossypol, meadowsweet, fe-verfew, beta glucan, pentosan, pentoxifylline, cilostazol, erlotinib, pemetrexed, methotrex-ate, pralatrexate. Individuals with uncontrolled renal insufficiency or renal failure. History of allergic reactions attributed to naproxen or aspirin. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncon-trolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac ar-rhythmia, or psychiatric illness/social situations that would limit compliance with study require-ments. Pregnant, breast-feeding, or women of childbearing potential unwilling to use a reliable contra-ceptive 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 or aspirin, breastfeeding should be discontinued if the mother is treated with naproxen. Inclusion of Women and Minorities: -Participants will be adult men and women of all races and ethnic groups, who are at least 18 years old, and who are deemed eligible for this trial. Children will not be recruited to the trial. Our minority recruitment strategies will include identifying participants through the University of Texas MD Anderson Cancer Center Familial High-Risk Gastrointestinal Cancer Clinic and Weill Cornell Med-ical College. We will advertise the study on minority and other national websites.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Eduardo Vilar-Sanchez, MD
Phone
(713) 563-4743
Email
evilar@mdanderson.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eduardo Vilar-Sanchez, MD
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eduardo Vilar Sanchez, MD
First Name & Middle Initial & Last Name & Degree
Eduardo Vilar Sanchez, MD

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
MD Anderson Cancer Center

Learn more about this trial

A Phase IIa Randomized, Double-Blinded Clinical Trial of Naproxen or Aspirin for Cancer Immune Interception in Lynch Syndrome

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