E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
PIK3CA mutated colon cancer |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective of the trial 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. |
L’objectif de cette étude est de montrer un bénéfice statistiquement significatif et cliniquement pertinent en terme de survie sans récidive de la prise journalière d’une dose de 100 mg d’aspirine pendant 3 ans chez des patients avec cancer colorectal de stade II et III. |
Het doel van deze studie is om een statistisch significant en klinisch relevant voordeel aantonen betreffende overleving zonder recidief met dagelijkse inname van een dosis aspirine van 100 mg gedurende 3 jaar bij patiënten met colorectale kanker in stadia II en III. |
|
E.2.2 | Secondary objectives of the trial |
Secondary endpoints of the trial are:
• Time to recurrence (TTR)
• Overall survival (OS)
• Cancer-specific survival (CSS)
• Adverse events (AEs) |
Critères d’évaluation secondaires:
• Temps jusqu’à récidive
• Survie totale
• Survie spécifique au cancer du côlon
• Effet secondaires
|
Secundaire eindpunten:
• Tijd tot recidief
• Totale overleving
• Colonkanker-specifieke overleving
• Bijwerkingen
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- Tumoral expression of COX-2 (Version 1.0, 05 June 2015)
- PI3K Downstream signaling (Version 1.0, 05 June 2015)
- Tumoral Expression of HLA class I Antigen (Version 1.0, 05 June 2015)
- Tumoral BRAF V600E mutations and microsatellite instability (Version 1.0, 05 June 2015)
- Germline genetics (Version 1.0, 05 June 2015)
The objective of the ancillary substudies of SAKK 41/13 is to explore individual patient’s tumor tissue and peripheral blood for important predictive (COX-2 overexpression by immunohistochemistry (IHC), HLA class I antigen expression, germline genetics) and prognostic (BRAF V600E mutations, tumoral MSI status) factors. This will allow to gain a comprehensive understanding of the therapeutic impact of low-dose aspirin in this group of patients. Biobanks for both tumor tissue and peripheral blood will be implemented to permit future research on colon cancer. |
|
E.3 | Principal inclusion criteria |
1 Written informed consent according to ICH/GCP regulations before inclusion and prior to any trial-related investigations.
2 Histologically confirmed diagnosis of adenocarcinoma of the colon.
3 Stage II (pT3/T4 N0 cM0) or stage III (pTx pN+ cM0) colon cancer.
4 Availability of cancer tissue for central molecular testing.
5 Presence of predefined, activating PIK3CA mutation in exons 9 or 20 (centrally assessed, see section 17).
6 Complete resection of the primary tumor (R0) within 10 weeks maximum before registration.
7 WHO performance status 0-2 (see Appendix 3).
8 Age between 18–80 years.
9 Adequate hematological values: hemoglobin ≥ 80 g/L, platelets ≥ 50 x 10^9/L.
10 Adequate hepatic function: total bilirubin ≤1.5xULN, AST ≤2.5xULN, ALT ≤2.5xULN, AP ≤2.5xULN.
11 Calculated creatinine clearance > 30 mL/min, according to the formula of Cockcroft-Gault (see Appendix 2).
12 Women with child-bearing potential are using effective contraception (see 9.6), 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. |
- Cancer du côlon histologiquement confirmé.
- Stade II (pT3/T4 N0 cM0) ou stade III (pTx pN+ cM0).
- Mutation de PIK3CA activant dans l’exon 9 ou 20.
- État après résection curative (RO) en l’espace de 10 semaines après l’enregistrement.
- Statut de performance adéquat (PS 0-2) et valeurs hématologiques adéquates.
|
- Histologisch bevestigde colonkanker.
- Stadium II (pT3/T4 N0 cM0) of stadium III (pTx pN+ cM0).
- Mutatie in exon 9 of 20 van het PIK3CA-gen.
- Toestand na curatieve resectie (RO) binnen 10 weken na registratie.
- Voldoende performance status (PS 0-2) en afdoende hematologische waarden.
|
|
E.4 | Principal exclusion criteria |
1 Previous or concomitant malignancy within 3 years of registration, except for adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer.
2 Multiple adenocarcinomas of the colon.
3 Rectal cancer (defined as distance from anal verge to proximal/oral tumor edge ≤15 cm).
4 Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV (see Appendix 4), unstable angina pectoris, history of myocardial infarction) within three months prior to registration.
5 Systemic rheumatic diseases or degenerative disorders affecting the musculoskeletal system with a relevant risk of requiring treatment with NSAIDs in the future.
6 Comorbidities that require regular (i.e. more than 3x per month, any dose) intake of acetylsalicylic acid or other NSAIDs or COX-2 inhibitors.
7 Clinically relevant upper gastrointestinal bleeding within 12 months prior to registration.
8 Presence of any bleeding disorder that is an absolute contraindication to the use of aspirin.
9 General tendency to hypersensitivity and history of asthma triggered by salicylates of substances with a similar mechanism of action, and non-steroidal anti-inflammatory drugs in particular.
10 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).
11 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).
12 Psychiatric disorder precluding understanding of trial information, giving informed consent or interfering with compliance for oral drug intake.
13 Any familial, sociological or geographical condition potentially hampering proper staging and compliance with the trial protocol.
14 Known or suspected hypersensitivity to any component of the trial drug or any agent given in association with this trial.
15 Known galactose-1-phosphate uridyl transferase deficiency, UDP galactose 4 epimerase deficiency, galactokinase deficiency, Fanconi-Bickel syndrome, congenital lactase deficiency or glucose-galactose malabsorption (due to lactose-containing placebo).
16 Any concomitant drugs contraindicated for use with the trial drug according to the approved product information. |
- Patients avec cancer du rectum.
- Maladie cardiovasculaire sévère et non contrôlée
- Hémorragie gastro-intestinale haute en l’espace de 12 semaines avant l’enregistrement.
- Maladie hématologique impliquant une contre-indication absolue pour la prise d’aspirine.
- Prise régulière d’aspirine ou d’anti-inflammatoires non stéroïdiens (AINS) ou d’inhibiteur de la cyclooxygénase (inhibiteur de la COX-2).
- Maladies rhumatismales contre lesquelles des AINS sont très probablement utilisés.
- Traitement concomitant avec d’autres médicaments expérimentaux. |
- Patiënten met rectumkanker.
- Ernstige en ongecontroleerde cardiovasculaire ziekte
- Bovenste maagdarmkanaalbloeding binnen 12 weken vóór registratie.
- Hematologische aandoening met een absolute contra-indicatie voor aspirine.
- Regelmatige inname van aspirine of niet-steroïdale ontstekingsremmers (NSAID’s) of cyclo-oxygenaseremmer (COX-2-remmer).
- Reumatische aandoeningen waarvoor zeer waarschijnlijk NSAID’s ingenomen worden.
- Gelijktijdige behandeling met andere experimentele geneesmiddelen. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the trial is:
Disease-free survival (DFS) |
Le critère d’évaluation primaire est la survie sans cancer. |
Het primaire eindpunt is de overleving zonder kanker. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
DFS: time from surgery until one of the following events, whichever comes first: recurrence, second cancer, death due to any reason; evaluation by CT every 12 months |
|
E.5.2 | Secondary end point(s) |
Secondary endpoints of the trial are:
Time to recurrence (TTR)
Overall survival (OS)
Cancer-specific survival (CSS)
Adverse events (AEs) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
TTR: time from surgery until recurrence or death due to colon cancer.
OS: time from surgery until death from any cause.
CSS: time from surgery until death due to colon cancer, whether due to the original tumor or to a second primary same cancer.
AEs: continuously throughout study. AEs will be assessed according to NCI CTCAE v4.0. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Germany |
Hungary |
Switzerland |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 10 |