Chemotherapy and Immunotherapy as Treatment for MSS Metastatic Colorectal Cancer With High Immune Infiltrate
- Conditions
- Microsatellite StableColorectal Cancer MetastaticHigh Immune Infiltrate
- Interventions
- Registration Number
- NCT04262687
- Lead Sponsor
- Federation Francophone de Cancerologie Digestive
- Brief Summary
About 85% of cases of non-metastatic colorectal cancer (CRC) are related to chromosomal instability and have a proficient DNA Mismatch-Repair system (pMMR); which are also called CRC with microsatellite stability (MSS). Other CRC, i.e. 15%, are "microsatellite unstable" (MSI) with deficient DNA Mismatch-Repair system (dMMR). These latter are characterised by generation of many neo-antigens, which result in a high anti-tumour immune response and a high peri- and/or intra-tumour lymphocyte infiltration (TIL). Investigators recently showed, with a prospectively validated immune score, that 14% of localised MSS/pMMR CRC are also highly infiltrated by CD3+ lymphocytes. This same immune score has made it possible to measure high lymphocyte infiltration in hepatic metastases, in particular, in patients treated with XELOX/FOLFOX.
Pembrolizumab, an anti-PD1 monoclonal antibody (programmed death-1) is an immune checkpoint inhibitor (ICI) of PD1/PD-L1 axis, recently approved in many cancers. Anti-PD1 antibodies have recently been reported as being very effective in patients with dMMR metastatic CRC (mCRC). In the study by Le DT et al. pMMR mCRC did not seem to benefit from anti-PD1 antibodies. However, it is possible that 20% of pMMR mCRC with a high CD3+ infiltrate in the tumour may be a subgroup of pMMR mCRC sensitive to ICI, as is the case for dMMR mCRC. Lastly, immunogenic cell death induced by chemotherapy, such as oxaliplatin, can increase the efficacy of ICI.
The prognostic value of lymphocyte infiltrate has been demonstrated in CRC by several teams. However, no validated test is used in routine clinical practice. Previously, investigators described an automated and reproducible method for analysis of TIL and investigators validated it for clinical use. Automated tests evaluating TIL are performed on virtual slides and have showed that, out of 1,220 tumours tested, 20% were highly infiltrated by CD3+ T cells. Patients presenting with a pMMR CRC with a high immune infiltrate had a better progression-free survival (HR=0.70; p=0.02). An immunoscore® described by Galon et al. has also a high prognostic value in CRC and is based on CD3+ and CD8+ T cells infiltration in the center and periphery of the tumour. Finally, approximately 14% of tumours with a high immune infiltrate have been found in patients with metastatic CRC.
Investigators formulated the hypothesis that patients with a pMMR CRC with a high immune infiltrate can be sensitive to ICI . Therefore, blocks of resected primary tumour will be collected and analysed prospectively. For each patient, slides containing tumour tissue and adjacent non-tumour tissue will be analysed using two techniques : immunoscore® and TuLIS score.It consist in Immunohistochemistry with CD3 and CD8 staining. Slides will be scanned and analysed by image analysis as previously described . Tumours will then be classified as having a "high" or "low" immune response according to type of lymphocyte infiltrate, which is independent of pre-analytic conditions. Only patients with a high immune response will be eligible for the POCHI trial. Other biomarkers will be analysed like other immune populations or mutational load. If investigators identify an immune score which seems clinically relevant to predict sensitivity to ICI in pMMR mCRC, this will make it possible to plan a randomised phase III trial comparing chemotherapy and anti-angiogenic antibody versus chemotherapy and anti-angiogenic antibody plus pembrolizumab in patients with a pMMR mCRC with a high immune score and/or a hypermutated genotype.
Investigators choose PFS at 10 months as primary endpoint in POCHI trial because it is a surrogate marker of OS. Actually median PFS in first-line setting with a doublet plus a biological agent is range from 8 to 11 months in unresectable mCRC, corresponding to a PFS of 50% at 10 months. The alternative clinical hypothesis to obtain 70% of patients alive and without progression at 10 months is ambitious and currently not achieved with current chemotherapies plus a biological agent. Up until now there is no data concerning survivals outcomes of patients with a MSS mCRC with high immune infiltration score.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 55
- Age ≥ 18 years
- 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 scores 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
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Immunotherapy + chemotherapy Pembrolizumab Xelox bevacizumab plus pembrolizumab every 3 weeks up until disease progression, unacceptable toxicity, refusal by the patient, withdrawal of consent, pregnancy or decision by the investigator. Immunotherapy + chemotherapy Bevacizumab Xelox bevacizumab plus pembrolizumab every 3 weeks up until disease progression, unacceptable toxicity, refusal by the patient, withdrawal of consent, pregnancy or decision by the investigator. Immunotherapy + chemotherapy Capecitabine Xelox bevacizumab plus pembrolizumab every 3 weeks up until disease progression, unacceptable toxicity, refusal by the patient, withdrawal of consent, pregnancy or decision by the investigator. Immunotherapy + chemotherapy Oxaliplatin Xelox bevacizumab plus pembrolizumab every 3 weeks up until disease progression, unacceptable toxicity, refusal by the patient, withdrawal of consent, pregnancy or decision by the investigator.
- Primary Outcome Measures
Name Time Method The rate of patients alive and without progression at 10 months after inclusion 10 months after inclusion Progression is evaluated by CT scan, according to RECIST criteria (version 1.1) definition by the investigator. Death was also considered as an event (all causes). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions compared the little sum of diameters observed during the study (NADIR), or a measurable increase in a non-target lesion, or the appearance of new lesions
- Secondary Outcome Measures
Name Time Method Overall survival Up to 2 years after the end of the treatment Overall survival is defined as the time from the date of the patient's inclusion to the patient's death (all causes). For alive patients the date of the latest news is taken into account
Histological response in case of secondary resection Up to 2 years after the end of the treatment Response evaluated according to the TRG (Rubbia-Brandt L et al. Annals Oncol 2007), for patients who underwent a secondary resection
Trial Locations
- Locations (88)
Chu - Hôpital Saint Antoine
🇫🇷Paris, France
Privé - Cac - Institut Gustave Roussy
🇫🇷Villejuif, France
Privé - Cac - Institut de Cancerologie de Lorraine
🇫🇷Vandœuvre-lès-Nancy, France
Chu - Hôpital Bradois
🇫🇷Vandœuvre-lès-Nancy, France
Chu - Hôpital Paul Brousse
🇫🇷Villejuif, France
Chu - Hôpital Henri Mondor
🇫🇷Créteil CEDEX, France
Ch - Chic de Créteil
🇫🇷Créteil, France
Privé - Clinique Du Bois
🇫🇷Lille, France
Privé - Centre Cario Hpca
🇫🇷Plérin, France
Chu - Hôpital Sud
🇫🇷Amiens, France
Ch - Centre Hospitalier D'Abbeville
🇫🇷Abbeville, France
Privé - Clinique de L'Europe
🇫🇷Amiens, France
Privé - Hôpital Privé Pays de Savoie
🇫🇷Annemasse, France
Privé - Ico - Site Paul Papin
🇫🇷Angers, France
Privé - Hôpital Privé D'Antony
🇫🇷Antony, France
Ch - Hôpital Henri Duffaut
🇫🇷Avignon, France
Ch - Centre Hospitalier de Beauvais
🇫🇷Beauvais, France
Ch - Centre Hospitalier de La Côte Basque
🇫🇷Bayonne CEDEX, France
Prive - Institut Du Cancer Avignon Provence
🇫🇷Avignon, France
Privé - Clinique Capio Balharra
🇫🇷Bayonne, France
Chu - Hôpital Jean Minjoz
🇫🇷Besançon, France
Privé - Cac - Clinique Bergonié
🇫🇷Bordeaux, France
Privé - Polyclinique Bordeaux Nord
🇫🇷Bordeaux CEDEX, France
Privé - Clinique Tivoli
🇫🇷Bordeaux, France
Ch - Hôpital Duchenne
🇫🇷Boulogne-sur-Mer, France
Chu - Hôpital Ambroise Paré - Service Anatomie Pathologique
🇫🇷Boulogne, France
Privé - Clinique Pasteur Lanroze Cfro
🇫🇷Brest, France
Chu - Hôpital Morvan - Institut de Cancérologie
🇫🇷Brest, France
Ch - Centre Hospitalier de Béziers
🇫🇷Béziers, France
Privé - Cac - Centre Francois Baclesse
🇫🇷Caen, France
Prive - Polyclinique Du Parc Caen
🇫🇷Caen, France
Privé - Centre Maurice Tubiana
🇫🇷Caen, France
Privé - Hôpital Privé Paul D'Egine
🇫🇷Champigny-sur-Marne, France
Privé - Infirmerie Protestante de Lyon
🇫🇷Caluire-et-Cuire, France
Privé - Médipole de Savoie
🇫🇷Challes-les-Eaux, France
Ch - Centre Hospitalier de Cholet
🇫🇷Cholet, France
Chu - Hôpital Estaing
🇫🇷Clermont Ferrand, France
Ch - Ghpso - Site de Creil
🇫🇷Creil, France
Ch - Hôpitaux Civils de Colmar
🇫🇷Colmar, France
Privé - Clinique Saint Come
🇫🇷Compiègne CEDEX, France
Privé - Clinique de Flandre
🇫🇷Coudekerque-Branche, France
Chu - Hôpital François Mitterrand
🇫🇷Dijon CEDEX, France
Privé - Cac - Centre Georges-Francois Leclerc
🇫🇷Dijon, France
Ch - Chd Vendée
🇫🇷La Roche-sur-Yon, France
Privé - Polyclinique de Blois - 3Eme Etage
🇫🇷La Chaussee St Victor, France
Privé - Hôpital Franco Britannique
🇫🇷Levallois-Perret, France
Chu - Centre Hospitalier Dupuytren
🇫🇷Limoges, France
CH - GROUPE HOSPITALIER DE La Rochelle RE AUNIS
🇫🇷La Rochelle, France
Ch - Chbs - Hôpital Du Scorff
🇫🇷Lorient CEDEX, France
Privé - Hôpital Europeen
🇫🇷Marseille CEDEX 03, France
Chu - Hôpital La Timone
🇫🇷Marseille CEDEX 5, France
Privé - Hôpital Jean Mermoz
🇫🇷Lyon, France
Privé - Haliodx
🇫🇷Marseille, France
Privé - Hôpital Saint Joseph
🇫🇷Marseille, France
Ch - Ghi - Groupe Hospitalier de L'Est Francilien - Site de Meaux
🇫🇷Meaux, France
Ch - Hôpital Layné
🇫🇷Mont-de-Marsan, France
Privé - Centre Azureen de Cancerologie
🇫🇷Mougins, France
Privé - Hôpital Prive Arnault Tzanck
🇫🇷Mougins, France
Chu - Hôpital Europeen Georges Pompidou
🇫🇷Paris, France
Privé - Polyclinique de Gentilly
🇫🇷Nancy, France
Privé - Institut Mutualiste Montsouris
🇫🇷Paris, France
Privé - Groupe Hospitalier Diaconesses Croix Saint Simon
🇫🇷Paris, France
Chu - Hôpital Saint-Louis
🇫🇷Paris, France
Chu - Hôpital Carémeau
🇫🇷Nîmes, France
Privé - Polyclinique Francheville
🇫🇷Perigueux, France
Ch - Centre Hospitalier de Pau
🇫🇷Pau CEDEX, France
Chu - Hôpital Haut Lévêque
🇫🇷Pessac, France
Ch - Centre Hospitalier Saint-Jean
🇫🇷Perpignan, France
Chu Lyon Sud - Pierre Benite
🇫🇷Pierre-Bénite, France
Chu - Centre Hospitalier Universitaire de Poitiers - La Miletrie
🇫🇷Poitiers, France
Ch - Chic de Quimper
🇫🇷Quimper, France
Chu - Centre Hospitalier Universitaire Robert Debre
🇫🇷Reims CEDEX, France
Privé - Cac - Institut Jean Godinot
🇫🇷Reims, France
Chu - Centre Hospitalier Universitaire Pontchaillou
🇫🇷Rennes CEDEX 9, France
Privé - Clinique Saint-Grégoire
🇫🇷Saint-Grégoire, France
Ch - Hôpital Drome Nord
🇫🇷Romans-sur-Isère, France
Ch - Centre Hospitalier de Saint-Malo
🇫🇷Saint-Malo, France
Privé - Cac - Ico - Site René Gauducheau
🇫🇷Saint-Herblain, France
Privé - Polyclinique Saint-Claude
🇫🇷Saint-Quentin, France
Chu - Centre Hospitalier Universitaire de Saint Etienne - Hôpital Nord - Service Hge
🇫🇷Saint-Priest-en-Jarez, France
Privé - Clinique Charcot
🇫🇷Sainte-Foy-lès-Lyon, France
Privé - Clinique Sainte Anne
🇫🇷Strasbourg, France
Chu - Hôpital Foch
🇫🇷Suresnes, France
Privé - Cac - Paul Strauss / Institut de Cancérologie de Strasbourg Europe
🇫🇷Strasbourg, France
Privé - Polyclinique de L'Ormeau
🇫🇷Tarbes, France
Chu - Hôpital Trousseau
🇫🇷Tours CEDEX 9, France
Ch - Hôpital Sainte Musse
🇫🇷Toulon, France
Ch - Centre Hospitalier de Valenciennes
🇫🇷Valenciennes, France