| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| MICROSATELLITE STABLE (MSS) METASTATIC COLORECTAL CANCER AND A HIGH IMMUNE INFILTRATE |
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| E.1.1.1 | Medical condition in easily understood language |
| METASTATIC COLORECTAL CANCER WITH SPECIFIC MOLECULAR PROFIL (MSS) AND A HIGH IMMUNE INFILTRATE |
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| 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 evaluate the efficacy of pembrolizumab in combination with XELOX and bevacizumab as 1st line treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC) with a high immune infiltrate. Efficacy will be determined by analysis of the number of patients alive and without radiological and/or clinical progression at 10 months (based on RECIST 1.1 criteria evaluated by the investigator). |
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| E.2.2 | Secondary objectives of the trial |
- Overall survival (median)
- Serious adverse events evaluated according to NCI-CTC v4.0
- Histological response in case of secondary resection (TRG criteria)
- Secondary resection rate (R0 and R1)
- Outcome of tumour markers (CEA and CA19.9)
Evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria):
- Percentage of patients alive and without progression at 10 months (centralised review)
- Progression-free survival (median)
- Time to progression
- Time to objective response
- Best response during treatment
- Depth of response
- Early tumour shrinkage at 9 weeks
Evaluated according to centralised review according to iRECIST criteria:
- Percentage of patients alive and without progression at 10 months
- Progression-free survival (median)
- Time to progression
- Early tumour shrinkage at 9 weeks
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| 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 |
| The ancillary study on biological samples (blood and stool) and tumour samples (primary tumours) will consist at least of analysis of histological (immune score, immunohistochemistry of PD-L1 and PD-L2), phenotypal (circulating lymphocytes and gut microbiota) and molecular biomarkers (circulating tumour DNA, mutational load, expression and/or amplification of PD-L1 and PD-L2). The primary objective of these studies is to identify prognostic biomarkers or predictive biomarkers of response to therapy with an immune checkpoint inhibitor. We are seeking to detect an association between the hypermutated characteristic, a high immune response and clinical response to anti-PD1 therapy (pembrolizumab), as described in other tumours. |
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| E.3 | Principal inclusion criteria |
- Age ≥ 18 years
- Both MSS and pMMR metastatic colorectal adenocarcinoma (metachronous or synchronous metastases), histologically proven
- Patients who have had chemotherapy (neo-adjuvant or adjuvant) or radiotherapy (neo-adjuvant or adjuvant) for the treatment of primary tumor or metastatic resected disease R0 can be included if they have a recurrence more than 6 months after the end of this treatment.
- High immune response defined as the immune infiltration score obtained on the primary tumour (resection of primary tumour containing at least 2 mm of tumour-free margin between the tumour and non-tumour area)
- Unresectable cancer with at least one measurable metastatic target according to RECIST v1.1 criteria
- WHO PS ≤ 1
- Absence severe neuropathy (≥ grade 2) (chemo-induced or not)
- Life expectancy > 3 months
- Adequate haematological function: neutrophils > 1,500 /mm3, platelets > 100,000/mm3, Hb > 9 g/dL
- Adequate liver function: AST/ALT ≤ 5xULN, total bilirubin ≤ 2xULN, Alkaline phosphatase ≤ 5xULN
- Creatinine clearance > 50 mL/min according to the MDRD formula
- Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour
- Patient who is a beneficiary of the social security system
- Information provided to patient and signature of the informed consent form
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| E.4 | Principal exclusion criteria |
- Active infection requiring intravenous antibiotics at day 1 of cycle 1
- Active or untreated central nervous system metastases
- Another concomitant cancer or history of cancer during the last 5 years, except for carcinoma in situ of the uterine cervix or a basal cell or squamous cell skin carcinoma or any other carcinoma in situ considered as cured
- Previous bone marrow allogenic stem cell transplantation or previous organ transplantation
- History of idiopathic pulmonary fibrosis, medicinal product-related pneumonia or proof of active pneumonia or pneumonitis on a chest CT-scan prior to therapy
- HIV infection, active hepatitis B or C infection, active tuberculosis
- Colorectal cancer with microsatellite instability (dMMR and/or MSI)
- Patient eligible for curative treatment (resection and/or thermal ablation according to the opinion of the local multidisciplinary tumour meeting board)
- Patient with only primary tumour biopsies available or only a sample of a metastasis (no surgical resection of the primary tumour)
- Previous treatment with anti-PD1 or anti-PDL1 or another immunotherapy
- An auto-immune disease which may worsen during treatment with an immune-stimulating agent (patients with type I diabetes, vitiligo, psoriasis, hypo or hyperthyroidism not requiring immunosuppressant therapy are eligible)
- Long-term immunosuppressant therapy (patients requiring corticosteroid therapy are eligible if administration at a dose ≤ 10 mg prednisone equivalent dose per day, administration of steroids by a route of administration resulting in minimal systemic exposure (cutaneous, rectal, ocular or inhalation) is authorised)
- Known severe hypersensitivity to monoclonal antibodies, to one of the medicinal products used or to one of the excipients in the products used or a history of anaphylactic shock or of uncontrolled asthma
- Vaccinations (live vaccine) within 30 days prior to start of treatment
- Dihydropyrimidine Dehydrogenase (DPD) deficiency defined by uracilemy level ≥ 16 ng/mL
- QT/QTc interval > 450 msec in men and > 470 msec in women
- One of the following disorders during the 6 months prior to inclusion: myocardial infarction, unstable/severe angina pectoris, coronary artery bypass grafting, NYHA class II, III or IV congestive heart failure, stroke or transient ischaemic attack
- All uncontrolled progressive disorders during the last 6 months: hepatic insufficiency, renal insufficiency, respiratory insufficiency, arterial hypertension
- History of an inflammatory digestive disease, obstruction or sub-obstruction not resolved with symptomatic treatment
- Peptic ulcer disease not healed before the treatment
- Not controlled HTA
- Patient already enrolled in another therapeutic trial with an ongoing investigational drug or whose treatment ended less than 4 weeks before inclusion
- Absence of effective contraception in patients (male and/or female patients) of childbearing potential, a pregnant or breastfeeding woman, women of childbearing potential and who have not had a pregnancy test
- Impossibility to submit to medical follow-up of the trial due to geographic, social or psychological reasons
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the percentage of patients alive and without progression at 10 months. Progression is defined by:
- radiological progression evaluated by the investigator according to RECIST v1.1 criteria.
- death, whatever the cause
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after last inclusion |
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| E.5.2 | Secondary end point(s) |
- Overall survival: is defined as time between date of inclusion and date of death of patient (whatever the cause) or date of last news if patient is alive.
- Grades 3 – 4 adverse events: will be evaluated according to NCI-CTC v4.0 criteria and described by maximum grade based on total duration of treatment and 30 days after treatment.
- Secondary resection rate (R0 and R1): is defined as the percentage of patients who underwent surgery on their metastatic lesions after the protocol treatment.
- Histological response in case of secondary resection: is evaluated according to the TRG (Rubbia-Brandt L et al. Annals Oncol 2007), in patients who underwent a secondary resection. This response is evaluated according to the various categories: TRG1/TRG 2/TRG 3/TRG 4/TRG 5.
- Outcome of tumour markers (CEA and CA19.9): the evolution of the markers will be analyzed by a graphic representation of the percentage change from baseline rate.
- Progression-free survival, according to the investigator (RECIST criteria) and in centralised review (RECIST and iRECIST criteria): is defined as the time between date of inclusion and date of a first radiological progression or the date of death of patient (whatever the cause). Patients alive without progression will be censured at date of last news. According to iRECIST criteria (see Appendix 4), progression will be considered as an event if it is confirmed. If the patient dies before confirmation of progression, the event will be considered as unconfirmed progression.
- The percentage of patients alive and without progression at 10 months (according to centralised review, RECIST and iRECIST criteria): progression is defined as radiological progression or death, whatever the cause. According to iRECIST criteria, the patient will be considered as in progression if progression is confirmed in the next 2 months.
- Time to progression, according to the investigator (RECIST criteria) and in centralised review (RECIST and iRECIST criteria): is defined as the time between date of inclusion and date of first progression (RECIST v1.1 criteria) or date of suspected progression if confirmed (iRECIST criteria).
- Time to an objective response (according to the investigator and in centralised review, RECIST criteria): is defined as the time between the date of inclusion and the date of a first objective response (complete response or partial response) during treatment. Patients with no imaging study (or if best response is not evaluable, or patients not treated) will not be taken into account in the analysis.
- Best response during treatment (according to the investigator and in centralised review, RECIST criteria): the best response is described by a percentage according to different categories: complete response (CR), partial response (PR), stability (S), progression (P) and not evaluable (NE). The best objective response is evaluated during treatment based on different imaging studies and according to RECIST v1.1 criteria.
- Depth of response (according to the investigator and in centralised review, RECIST criteria): is defined as the relative difference between the sum total of the largest diameters of target lesions in NADIR (RECIST v1.1: in the absence of new lesions or progression of non-target lesions) and the sum total of the largest diameters of target lesions at inclusion.
- Early tumour shrinkage at 9 weeks, according to the investigator (RECIST criteria) and in centralised review (RECIST and iRECIST criteria): is defined as the relative difference between the sum of the largest diameters of the target lesions at 9 weeks and the sum of different targets at inclusion. Tumour shrinkage corresponds to a relative difference > 20% with RECIST v1.1 criteria and > 30% with iRECIST.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoint up to 3 years
Safety endpoint : From Baseline up to 10 weeks after last administration |
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| 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 | Yes |
| 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 | 71 |
| 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
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| last visit of the last subject |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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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