PEMBROLIZUMAB for Microsatellite-stable metastatic colorectal cancer

Inclusion criteria

• {"criterion_text":"- ≥ 18 years\n- Both MSS and pMMR metastatic colorectal adenocarcinoma (metachronous or synchronous metastases), histologically proven\n- Patients who have had adjuvant/post-operative chemotherapy and/or post-operative radiotherapy for the treatment of their primary tumor or R0 resected metastatic lesions can be included if they have a recurrence more than 6 months after the end of this treatment\n- 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 nontumour area)\n- Unresectable cancer with at least one measurable metastatic target according to RECIST v1.1 criteria\n- WHO PS ≤ 1\n- Absence severe neuropathy (≥ grade 2) (chemo-induced or not)\n- Life expectancy > 3 months\n- Adequate haematological function: neutrophils > 1,500 /mm3, platelets > 100,000/mm3, Hb > 9 g/dL\n- Adequate liver function: AST/ALT ≤ 5xULN, total bilirubin ≤ 2xULN, Alkaline phosphatase ≤ 5xULN\n- Creatinine clearance > 50 mL/min according to the CKD-EPI formula\n- Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour\n- Patient who is a beneficiary of the social security system\n- Information provided to patient and signature of the informed consent form"}

Exclusion criteria

• {"criterion_text":"- Active infection requiring intravenous antibiotics at day 1 of cycle 1\n- All uncontrolled progressive disorders during the last 6 months: hepatic insufficiency, renal insufficiency, respiratory insufficiency, arterial hypertension\n- History of an inflammatory digestive disease, obstruction or subobstruction not resolved with symptomatic treatment\n- Active or untreated central nervous system metastases\n- Peptic ulcer disease not healed before the treatment\n- Patient already enrolled in another therapeutic trial with an ongoing investigational drug or whose treatment ended less than 4 weeks before inclusion\n- 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\n- Impossibility to submit to medical follow-up of the trial due to geographic, social or psychological reasons\n- Patients who have had neo-adjuvant treatment (chemotherapy or radiotherapy) for the treatment of primary tumor can not be included\n- 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\n- Previous bone marrow allogenic stem cell transplantation or previous organ transplantation\n- Previous treatment with anti-PD1 or anti-PDL1 or another immunotherapy\n- History of idiopathic pulmonary fibrosis, medicinal product-related pneumonia or proof of active pneumonia or pneumonitis on a chest CTscan prior to therapy\n- HIV infection, active hepatitis B or C infection, active tuberculosis\n- Colorectal cancer with microsatellite instability (dMMR and/or MSI)\n- Patient eligible for curative treatment (resection and/or thermal ablation according to the opinion of the local multidisciplinary tumour meeting board) and patient with RAS wild-type tumour for whom a tumour shrinkage with an anti-EGFR is necessary to perhaps obtain a XML File Identifier: IjpoCuOJiXEw1TRpi8rHlb0n7yE= Page 27/63 downstaging for a secondary surgery (according to the opinion of the local multidisciplinary tumour meeting board and/or at investigator's discretion)\n- Patient with only primary tumour biopsies available or only a sample of a metastasis (no surgical resection of the primary tumour)\n- 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)\n- 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)\n- 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\n- Vaccinations (live vaccine) within 30 days prior to start of treatment\n- Dihydropyrimidine Dehydrogenase (DPD) deficiency defined by uracilemy level ≥ 16 ng/mL\n- QT/QTc interval > 450 msec in men and > 470 msec in women\n- 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\n- Concomitant treatment with brivudine or brivudine within 4 weeks before capecitabine or 5FU initiation\n- Poor nutritional status"}

Primary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Percentage of patients alive and without progression at 10 months; progression defined as radiological progression evaluated by the investigator according to RECIST v1.1 criteria or death (any cause)."}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Time from date of inclusion to date of death (any cause) or date of last contact if alive."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Adverse events graded per NCI-CTC v4.0; reported as maximum grade during treatment and up to 30 days post-treatment."}
• {"endpoint_text":"- Secondary resection rate (R0 and R1): is defined as the percentage of patients who underwent surgery on their metastatic lesions after the protocol treatment.","definition_or_measurement_approach":"Proportion of patients undergoing secondary surgery on metastases (R0 or R1) after protocol treatment."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Histological tumour regression grade (TRG) per Rubbia-Brandt categories in patients having secondary resection."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Change from baseline in CEA and CA19.9 represented graphically as percent change."}
• {"endpoint_text":"- Progression-free survival, according to the investigator (RECIST criteria): defined as time between date of inclusion and date of a first radiological progression or date of death (whatever the cause). Patients alive without progression will be censured at date of last news. According to iRECIST criteria, progression will be considered as an event if it is confirmed. If the patient dies before confirmation, the event will be considered as unconfirmed progression.","definition_or_measurement_approach":"Time from inclusion to first radiological progression per investigator (RECIST v1.1) or death; censoring at last contact if no progression."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Centralised review assessment of percentage alive and without progression at 10 months per RECIST and iRECIST; progression = radiological progression or death; iRECIST requires confirmation within 2 months."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Time from inclusion to first progression per RECIST v1.1 (investigator) and central review (RECIST/iRECIST); iRECIST events require confirmation."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Time from inclusion to first objective response (CR or PR) per RECIST v1.1; patients without evaluable imaging excluded from analysis."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Categorical best objective response during treatment (CR, PR, SD, PD, NE) per RECIST v1.1 assessed by investigator and central review."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Relative difference between sum of largest diameters at nadir vs baseline per RECIST v1.1."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Relative change in sum of diameters at 9 weeks vs baseline; shrinkage threshold >20% (RECIST v1.1) or >30% (iRECIST)."}

France

Earliest CTIS Part Ii Submission Date

18-07-2024

Latest Decision Or Authorization Date

28-10-2025

Processing Time Days

467

Number Of Participants

55

Primary sponsor

Full Name

Fondation Franc.Cancerologie Digestive

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France