MICROSATELLITE STABLE (MSS) METASTATIC COLORECTAL CANCER AND A HIGH IMMUNE INFILTRATE
Conditions
Interventions
Product Name: pembrolizumab
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Other descriptive
Sponsors
Federation Francophone de Cancerologie Digestive
Eligibility
Sex/Gender
All
Inclusion criteria
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 =65 years) yes F.1.3.1 Number of subjects for this age range 44
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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).;Secondary Objective: -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 ;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 ;Timepoint(s) of evaluation of this end point: 12 months after last inclusion | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
France
Contacts
Public ContactBEZ Jérémie
Federation Francophone de Cancerologie Digestive
Outcome results
None listed