Adjuvant Aspirin Treatment for Colon Cancer Patients

Following complete resection of their primary tumor, potentially eligible stage II or stage III colon cancer patients will undergo central PIK3CA testing. Patients with somatic mutations will be 2:1 randomized to daily aspirin 100 mg versus placebo for a a maximum of 3 years or until disease recurrence, patient death or withdrawal of consent, whichever occurs first. Patients will be followed up for at least 3 years from the date of surgery.

The intake of aspirin or placebo is independent of adjuvant chemotherapy, and does not impact on the indication to give (or not to give) adjuvant chemotherapy.

Colorectal cancer is the third most common malignancy for both women and men and is responsible for almost 10% of all cancer death. Despite complete removal of the tumor and use of adjuvant chemotherapy, up to 25% of patients with stage II colon cancer and up to 50% of patients with stage III disease will suffer from recurrences, which is associated with poor prognosis.

Several retrospective observations have documented a favorable effect of long-term intake of oral aspirin for the prevention of colorectal cancer in different clinical situations. Regular intake of aspirin after the diagnosis of colorectal cancer may also be associated with a lower risk of colorectal cancer-specific and overall mortality. Two recent publications in prestigious medical journals provided retrospective evidence that patients with PIK3CA-mutated colon cancer may derive a very substantial benefit from daily oral aspirin. Both analyses showed a roughly 85% reduction of the risk for tumor relapse compared to patients who did not take aspirin. However, a potential selection bias in these retrospective analyses cannot be excluded with certainty. These extremely interesting and intriguing findings must be confirmed in a randomized controlled trial to potentially change clinical practice.

The trial objective is to demonstrate a statistically significant and clinically relevant disease-free survival benefit in stage II and III PIK3CA mutated colon cancer patients taking daily adjuvant aspirin for 3 years.

Patients with resected colon cancer stage II or stage III bearing somatic mutations in exon 9 or 20 of PIK3CA will be 2:1 randomized to daily adjuvant aspirin 100 mg versus placebo for a maximum of 3 years or until disease recurrence, patient death or withdrawal of consent, whichever occurs first. Patients will be followed up for at least 3 years from the date of surgery. The intake of aspirin or placebo is independent of adjuvant chemotherapy, and does not impact on the indication to give (or not to give) adjuvant chemotherapy.

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent according to ICH/GCP regulations before inclusion and prior to any trial-related investigations.
* Histologically confirmed diagnosis of adenocarcinoma of the colon.
* Stage II (pT3/T4 N0 cM0) or stage III (pTx pN+ cM0) colon cancer.
* Availability of cancer tissue for central molecular testing.
* Presence of predefined, activating PIK3CA mutation in exons 9 or 20 (centrally assessed).
* Complete resection of the primary tumor (R0) within 14 weeks maximum before registration.
* WHO performance status 0-2.
* Age between 18-80 years.
* Adequate hematological values: hemoglobin ≥ 80 g/L, platelets ≥ 50 x 109/L.
* Adequate hepatic function: total bilirubin ≤1.5xULN, AST ≤2.5xULN, ALT ≤2.5xULN, AP ≤2.5xULN.
* Calculated creatinine clearance \> 30 mL/min, according to the formula of Cockcroft-Gault.
* Women with child-bearing potential are using effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment. A negative pregnancy test before inclusion (within 7 days) into the trial is required for all women with child-bearing potential.

Exclusion Criteria:

* Previous or concomitant malignancy within 3 years of registration, except for adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer.
* Multiple adenocarcinomas of the colon.
* Rectal cancer (defined as distance from anal verge to proximal/oral tumor edge ≤15 cm).
* Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction) within three months prior to registration.
* Systemic rheumatic diseases or degenerative disorders affecting the musculoskeletal system with a relevant risk of requiring treatment with NSAIDs in the future.
* Comorbidities that require regular (i.e. more than 3x per month, any dose) intake of acetylsalicylic acid or other NSAIDs or COX-2 inhibitors.
* Clinically relevant upper gastro-intestinal bleeding within 12 months prior to registration.
* Presence of any bleeding disorder that is an absolute contraindication to the use of aspirin.
* General tendency to hypersensitivity and history of asthma triggered by salicylates or substances with a similar mechanism of action, and non-steroidal anti-inflammatory drugs in particular
* Any serious underlying medical condition, at the judgment of the investigator, which could impair the ability of the patient to participate in the trial (e.g. uncontrolled infection, active autoimmune disease, uncontrolled diabetes).
* Concurrent treatment with other experimental drugs or treatment in an interventional clinical trial within 30 days prior to trial entry. Concomitant use of adjuvant chemotherapy for stage III and high risk stage II colon cancer according to international treatment guidelines is allowed (chemotherapy regimens include intravenous 5-fluorouracil or oral capecitabine either alone or in combination with intravenous oxaliplatin).
* Psychiatric disorder precluding understanding of trial information, giving informed consent or interfering with compliance for oral drug intake.
* Any familial, sociological or geographical condition potentially hampering proper staging and compliance with the trial protocol.
* Known or suspected hypersensitivity to any component of the trial drug or any agent given in association with this trial.
* Known galactose-1-phosphate uridyl transferase deficiency, UDP galactose 4 epimerase deficiency, galactokinase deficiency, orFanconi-Bickel syndrome, congenital lactase deficiency,or glucose-galactose malabsorption (due to the lactose-containing placebo).
* Any concomitant drugs contraindicated for use with the trial drug according to the approved product information.