| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adenocarcinoma of the colon or of the upper rectum (supra-peritoneal) considered operable and histologically confirmed, localised, mutated BRAF V600E |
|
| E.1.1.1 | Medical condition in easily understood language |
| Colon or upper rectum cancer considered operable and presenting a mutation called BRAFV600E |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| To assess the rate of significant tumour regression (TRG 0 to 2 according to Ryan’s modified score of the AJCC 2010) with centralised review after neoadjuvant treatment with encorafenib and cetuximab, in patients with RAS wild type localised colon cancer (CC) and carriers of the BRAF V600E mutation. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the response rate in CT-scan according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumours) according to the investigator and centralised review
• To assess the post-operative complication rate
• To assess safety of the combination encorafenib and cetuximab according to the NCI-CTCAE v4.0 classification
• To assess dose intensity of cetuximab and compliance with encorafenib
• To assess progression-free survival (PFS) and overall survival (OS) at 2 and 3 years
• To assess quality of life (EQ5D)
|
|
| 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 |
| Biological and tissue sample collections for analysis of tumour response will be comprised, in particular, with study of circulating tumour DNA prior to treatment, during treatment, before surgery and after surgery |
|
| E.3 | Principal inclusion criteria |
- Informed consent signed and dated by the patient and the investigator
- Age ≥18 years and ≤ 75 years at time of informed consent
- Adenocarcinoma of the colon or of the upper rectum (supra-peritoneal) considered operable and histologically confirmed, localised, mutated BRAF V600E determined in a biopsy specimen and resectable after CT-scan assessment.
Remark: Centralised analysis of BRAF status will be performed in order to confirm the existence of the mutation concomitantly with the 1st cycle of therapy
- Tumour stage rT4 or rT3 with ≥ 5 mm extra-mural extension in a CT-scan.
o rT3 with high risk: Tumour spread from the peripheral serosa and extension to the adjacent peritoneal fat of more than 5 mm in its longest diameter (both axial and coronal planes)
o rT4: Extension to an adjacent organ
- Patient able to provide a sufficient quantity of representative tumour sample (slides or extracted tumor DNA) for centralised analysis of RAS and BRAF mutational status.
- WHO performance status 0 or 1
- Haematological function considered satisfactory:
o Polymorphonuclear neutrophils (PMN) ≥ 1,500/mm3
o Platelets ≥ 100,000/mm3
o Hb ≥ 9g/dL
- Creatinine clearance > 50 mL/min (according to MDRD formula).
- Serum levels of magnesium within normal limits of the centre.
- Total serum bilirubin ≤ 25 µmol/L, ALT and/or AST ≤ 2.5 x ULN.
- Cardiac function considered satisfactory:
o Corrected mean QT interval for heart rate according to the Fridericia formula (QTcF) ≤ 480 ms.
- Patient able to take medicinal products by mouth (OD).
- Female Patients postmenopausal for at least one year or surgically infertile for at least 6 weeks, or effective contraception for male and female patients of childbearing potential for 2 months after the end of the investigational treatments
- A negative pregnancy test for inclusion for all female patients of child-bearing potential.
- Patient covered by a plan of the French Social Security system.
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|
| E.4 | Principal exclusion criteria |
- Existence of distant metastases or adjacent nodules of peritoneal carcinosis (M1).
- Existence of a dual-tumour location.
- Peritonitis (secondary to perforation of the tumour) or symptomatic colonic occlusion or a temporary colostomy to prevent a sub-occlusion.
- Patient in whom an indication for radiotherapy exists based on the multidisciplinary meeting/board pre-operatively.
- Previous treatment with a BRAF inhibitor, cetuximab or other anti-EGFR treatment.
- History of acute or chronic pancreatitis within the 6 months prior to start of the study treatment.
- A history of chronic inflammatory bowel disease requiring treatment (with immuno-modulators or immuno-suppressants) ≤ 12 months before start of study treatment.
- Patient with decreased cardiovascular function or clinically significant cardiovascular disease:
a. History of myocardial infarction, acute coronary syndrome (including unstable angina, coronary artery bypass grafting, coronary angioplasty or stent placement) ≤ 6 months prior to start of the study treatment.
b. Symptomatic congestive heart failure (CHF) (grade 2 or higher), history or current evidence of cardiac arrhythmia and/or a clinically significant conduction disorder ≤ 6 months prior to start of the study treatment, except atrial fibrillation with controlled heart rate and paroxysmal supra-ventricular tachycardia.
- Child-Pugh class B or C cirrhosis.
- Deterioration of gastro-intestinal function or a disease which may significantly impair the absorption of encorafenib,
e.g.: ulcer disease, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, small bowel resection
- A previous or concomitant malignant tumour within 5 years prior to the study.
Except for basal cell or squamous skin cancer, superficial cancer of the bladder, intra-epithelial carcinoma of the prostate, carcinoma in situ of the uterine cervix or any other malignant tumour which has been treated adequately and which has not recurred during the three years prior to entry in the study.
- A concomitant neuro-muscular disease associated with high levels of creatinine kinase (CK).
Remark: inflammatory muscular disease, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy.
- History of infection with human immunodeficiency virus (HIV).
- Active infection with hepatitis B or hepatitis C.
- Known existence of Gilbert syndrome
- Use of medicinal plants/dietary supplements or other medicinal products or foods that are potent inducing agents or inhibitors of cytochrome P450 (CYP) 3A4/5 ≤ 1 week before start of the study treatment.
- Known severe hypersensitivity reactions to monoclonal antibodies or BRAF-inhibitors (grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
- Participation in a clinical study with administration of an investigational product within 4 weeks or five times the half-life of the investigational product, according to the longest period, prior to the first dose of the study treatment.
- Persons who are deprived of their freedom or who are under guardianship.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is the tumour regression rate (TRG0 to TRG2) assessed with Ryan’s modified score from the AJCC 2010 (ref: Edge SB, et al. 3rd AJCC cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.) in the level of the primary tumour, after surgery and centralised review. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After surgery which should be done within 9 weeks after the first dose of treatment |
|
| E.5.2 | Secondary end point(s) |
• Overall safety of treatment will be assessed by:
o Treatment-related toxicities. They will be described according to system organ class and preferred term (NCI-CTCAE v4.0). The maximum grade of each toxicity will be chosen.
• The dose intensity of cetuximab will be calculated based on the doses prescribed in each cycle. Compliance with encorafenib will be calculated based on number of capsules dispensed, number of capsules returned at the following visit and time between 2 visits.
• Overall survival is defined as time between date of inclusion and date of death, whatever the cause. Patients lost to follow-up or alive at time of analysis will be censored at date of last news.
• Progression-free survival is defined as time between date of inclusion and date of local or loco-regional recurrence or metastatic spread or death, whatever the cause. The second cancers will not be taken into account as events. Patients who are alive and without recurrence will be censored at date of their last news.
• The response rate in CT-scan according to RECIST 1.1 criteria will be described according to the following modalities: Complete response, Partial response, Stable disease, Progression or not evaluable in a CT-scan prior to surgery.
• Post-operative morbidity and mortality will be collected during the 30 days after surgery.
• Peri-operative and post-operative complications, the main complications and its grade according to Clavien and Dindo score, deaths occurred during the 30 days after surgery will be described.
• Quality of life will be assessed according to the (EQ5D) questionnaire. Five scores are calculated based on this questionnaire: mobility, personal care, pain-discomfort, usual activity and anxiety-depression. They are defined on 5 levels. A visual analogue scale will also be described in each phase.
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
three months after treatment end
End of treatment
two and three years after treatment end
date of local or loco-regional recurrence or metastatic spread or death, whatever the cause. The second cancers will not be taken into account as events. Patients who are alive and without recurrence will be censored at date of their last news.
One month after surgery
Within forteen days of completion of neoadjuvant therapy |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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