Assessment of Direct Biomarkers of Aspirin Action to Develop a Precision Chemoprevention Therapy of Colorectal Cancer

Acetylsalicylic acid (ASA) seems the ideal colorectal cancer (CRC) chemoprevention agent. Several ongoing trials are testing the effect of ASA as co-therapy in CRC. The mechanisms of action, the appropriate dose and the ideal target population are unknown. The investigators have demonstrated that doses of 100 mg of ASA induce direct and partial but persistent acetylation of the cyclooxygenase (COX) isoenzyme COX-1 in the normal colorectal mucosa. The primary objective is to perform a study of aspirin by using a proteomic assay for comparing platelet COX-1 and CRC mucosal COX-1 after different doses of ASA. Secondary objectives are: the measurement of prostaglandin E2 (PGE2) and phosphorylated S6 protein (p-S6) levels in CRC mucosa, the assessment of indirect biomarker of aspirin action (serum thromboxane B2 (TXB2) and urinary levels of 11-dehydro-TXB2 (TX-M)), the evaluation of systemic biomarkers of inflammatory/tumorigenic COX-2 by assessing urinary levels of major metabolite of PGE2 (PGE-M). Methods: Phase II randomized clinical trial in 60 patients with newly diagnosed CRC in 3 groups of 20 patients receiving 100 or 300 mg/day, or 100 mg/12 hours of enteric-coated ASA for 3±1 weeks, prior to definitive treatment by surgery. Main outcome: Acetylation of COX-1 and COX-2. Eicosanoid levels in target organs. Expected results: Evidence for the current uncertainty about the mechanisms of action and the dose required to obtain the best chemopreventive effect with ASA in CRC. Confirm acetylation of COX as a key biomarker of efficacy with ASA.

Study Overview

• Status: Unknown
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: acetylsalicylic acid

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ángel Lanas Arbeloa, MD; Phone Number: 0034976765786; Email: angel.lanas@gmail.com

Study Locations

• Spain
  • Zaragoza, Spain, 50009
    • Recruiting
    • Hospital Clinico Universitario Lozano Blesa
    • Contact: Ángel Lanas Arbeloa, MD; Phone Number: 0034976765786; Email: angel.lanas@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age ≥ 18 < 80 years old
• recent diagnosis (< 48h) of rectum or colon cancer, established by endoscopy and later confirmed by anatomo-pathologic study
• normal coagulation values and biochemical vales without clinically significant deviations that, at the discretion of the investigator, may interfere with the study procedures

Exclusion Criteria:

• Allergy to ASA or to any other NSAID.
• Rectal cancer requiring neoadjuvant treatment within the two weeks following the beginning of ASA treatment.
• Previous use of ASA, NSAIDs, antiplatelet agents, corticosteroids or misoprostol within the 15 days prior to diagnosis and/or anticipation of need for treatment with any of these drugs during the study period. History of peptic ulcer disease or active peptic ulcer or any other gastrointestinal disease that may be considered a contraindication to the use of ASA, without the concomitant use of proton pump inhibitors.
• Diagnosis of bleeding disorders.
• Diagnosis of cancer (excluding non-melanoma skin cancer) within the previous 3 years.
• Conditions supposing serious comorbidity, excluding diabetes, and including respiratory, cardiac, hepatic and renal diseases.
• Active smoking.
• Pregnancy or breastfeeding.
• History of drug or alcohol abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 (100 mg/24h)	Drug: acetylsalicylic acid; Different dosage effect over platelet COX enzymes, non- neoplastic and neoplastic colonic tissues used as biomarkers of clinical efficacy in CRC chemoprevention
Experimental: Arm 2 (300 mg/24h)	Drug: acetylsalicylic acid; Different dosage effect over platelet COX enzymes, non- neoplastic and neoplastic colonic tissues used as biomarkers of clinical efficacy in CRC chemoprevention
Experimental: Arm 3 (100 mg/12h)	Drug: acetylsalicylic acid; Different dosage effect over platelet COX enzymes, non- neoplastic and neoplastic colonic tissues used as biomarkers of clinical efficacy in CRC chemoprevention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Assessment of changes in acetylation levels of COX enzymes in platelets and non-neoplastic and neoplastic colonic tissues	before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Assessment of changes in prostaglandin E2 (PGE2) levels in colorectal mucosa depending on drug dosis	before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment
Assessment of changes in phosphorylated S6 protein (p-S6) levels in colorectal mucosa depending on drug dosis	before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment
Assessment of changes in thromboxane B2 (TxB2) levels in urine as indirect systemic biomarker depending on drug dosis	before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment
Assessment of changes in urinary metabolite 11-dehydro-TxB2 (TX-M) levels as indirect systemic biomarker depending on drug dosis	before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment
Assessment of changes in major urinary metabolite of PGE2 (PEG-M) levels depending on drug dosis	before the beginning of the treatment and 3 ± 1 weeks of acetylsalicylic acid treatment

Collaborators and Investigators

• Sponsor: Instituto de Investigación Sanitaria Aragón
• Collaborators: G. d'Annunzio University; Instituto de Salud Carlos III; Hospital Clínico Universitario Lozano Blesa
• Investigators: Principal Investigator: Ángel Lanas Arbeloa, MD, Instituto de Investigación Sanitaria Aragón

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2019
• Primary Completion (Anticipated): May 1, 2020
• Study Completion (Anticipated): May 1, 2020

Study Registration Dates

• First Submitted: May 13, 2019
• First Submitted That Met QC Criteria: May 20, 2019
• First Posted (Actual): May 21, 2019

Study Record Updates

• Last Update Posted (Actual): May 21, 2019
• Last Update Submitted That Met QC Criteria: May 20, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: PI17/01109; 2018-002101-65 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No