Colon Cancer
Conditions
Keywords
Aspirin, colon cancer, stage II, stage III, PIK3CA, double-blind, placebo, Adjuvant Treatment
Brief summary
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.
Detailed description
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.
Interventions
DRUGAspirin
Aspirin 100 mg daily
DRUGPlacebo
Placebo
Sponsors
European Organisation for Research and Treatment of Cancer - EORTC
Central European Society for Anticancer Drug Research
Swiss Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival (DFS) | up to 7 years | The primary endpoint of this trial is DFS, defined as time from surgery until one of the following events, whichever comes first: * recurrence * second cancer * death due to any reason Patients not experiencing an event will be censored at the date of the last available tumor assessment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recurrence (TTR) | up to 7 years | TTR was calculated from surgery until recurrence or death due to colon cancer. Patients not experiencing an event or patients who died due to other reasons before experiencing an event were censored at the date of the last available tumor assessment. |
| Overall Survival (OS) | up to 7 years | OS was calculated from surgery until death from any cause. Patients not experiencing an event were censored at the last date they were known to be alive. |
| Cancer-specific Survival (CSS) | up to 7 years | CSS was calculated from surgery until death due to colon cancer, whether due to the original tumor or to a second primary same cancer. Patients who died due to other reasons were censored at the time of death. All other patients were censored at the last date they were known to be alive. |
| Adverse Events (AEs) | During treatment (median 22.1 months) | — |
Countries
Belgium, Germany, Hungary, Switzerland
Participant flow
Pre-assignment details
Screened (n=1040) PIK3CA-mutated (n=180) Randomized (n=113) Excluded (n=67): * Not meeting inclusion criteria (n=20) * Declined to participate (n=43) * Other reasons (n=4)
Participants by arm
| Arm | Count |
|---|---|
| Aspirin 100 mg Asprin 100 mg daily for maximum 3 years standard chemo if indicated
Aspirin: Aspirin 100 mg daily | 74 |
| Placebo Placebo daily for maximum 3 years standard chemo if indicated
Placebo: Placebo | 38 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Allocation | Withdrawal by Subject | 1 | 0 |
| Follow-up | Death | 5 | 4 |
| Follow-up | Lost to Follow-up | 6 | 5 |
Baseline characteristics
| Characteristic | Aspirin 100 mg | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 43 Participants | 19 Participants | 62 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants | 19 Participants | 50 Participants |
| Age, Continuous | 68 years | 65 years | 66 years |
| Race/Ethnicity, Customized Ethnicity African | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity Asian | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Ethnicity Caucasian | 67 Participants | 38 Participants | 105 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Other | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Belgium | 4 participants | 1 participants | 5 participants |
| Region of Enrollment Germany | 25 participants | 11 participants | 36 participants |
| Region of Enrollment Hungary | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Switzerland | 44 participants | 25 participants | 69 participants |
| Sex: Female, Male Female | 30 Participants | 18 Participants | 48 Participants |
| Sex: Female, Male Male | 44 Participants | 20 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 74 | 4 / 38 |
| other Total, other adverse events | 0 / 74 | 0 / 38 |
| serious Total, serious adverse events | 1 / 74 | 3 / 38 |
Outcome results
Primary
Disease-free Survival (DFS)
The primary endpoint of this trial is DFS, defined as time from surgery until one of the following events, whichever comes first: * recurrence * second cancer * death due to any reason Patients not experiencing an event will be censored at the date of the last available tumor assessment.
Time frame: up to 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin 100 mg | Disease-free Survival (DFS) | NA years |
| Placebo | Disease-free Survival (DFS) | NA years |
p-value: 0.11Log Rank
90% CI: [0.27, 1.22]
90% CI: [0.22, 1.46]
Secondary
Adverse Events (AEs)
Time frame: During treatment (median 22.1 months)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin 100 mg | Adverse Events (AEs) | Anemia | 0 Participants |
| Aspirin 100 mg | Adverse Events (AEs) | Colonic hemorrhage | 0 Participants |
| Aspirin 100 mg | Adverse Events (AEs) | Cranial fracture with intra cranial hemorrhage | 0 Participants |
| Aspirin 100 mg | Adverse Events (AEs) | Dizziness | 1 Participants |
| Placebo | Adverse Events (AEs) | Dizziness | 0 Participants |
| Placebo | Adverse Events (AEs) | Anemia | 1 Participants |
| Placebo | Adverse Events (AEs) | Cranial fracture with intra cranial hemorrhage | 1 Participants |
| Placebo | Adverse Events (AEs) | Colonic hemorrhage | 1 Participants |
Secondary
Cancer-specific Survival (CSS)
CSS was calculated from surgery until death due to colon cancer, whether due to the original tumor or to a second primary same cancer. Patients who died due to other reasons were censored at the time of death. All other patients were censored at the last date they were known to be alive.
Time frame: up to 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin 100 mg | Cancer-specific Survival (CSS) | NA years |
| Placebo | Cancer-specific Survival (CSS) | NA years |
Secondary
Overall Survival (OS)
OS was calculated from surgery until death from any cause. Patients not experiencing an event were censored at the last date they were known to be alive.
Time frame: up to 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin 100 mg | Overall Survival (OS) | NA years |
| Placebo | Overall Survival (OS) | NA years |
p-value: 0.3Log Rank
90% CI: [0.23, 2.13]
90% CI: [0.15, 2.43]
Secondary
Time to Recurrence (TTR)
TTR was calculated from surgery until recurrence or death due to colon cancer. Patients not experiencing an event or patients who died due to other reasons before experiencing an event were censored at the date of the last available tumor assessment.
Time frame: up to 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin 100 mg | Time to Recurrence (TTR) | NA years |
| Placebo | Time to Recurrence (TTR) | NA years |
p-value: 0.089Log Rank
90% CI: [0.21, 1.19]
90% CI: [0.2, 1.55]