Standard Chemotherapy vs Immunotherapie in 2nd Line Treatment of MSI Colorectal Mestastatic Cancer
- Conditions
- Metastatic Colorectal CancerMSI
- Interventions
- Drug: FOLFOX regimenDrug: FOLFIRI Protocol
- Registration Number
- NCT03186326
- Lead Sponsor
- Federation Francophone de Cancerologie Digestive
- Brief Summary
Immune chekpoints (ICI) are evaluated in many digestive cancers. Certain types of cancer appear to be rather refractory to ICI such as colorectal cancers (CRC). However, the MSI CRC representing approximately 15% of the CRCs exhibits a high mutational load which generates many potentially immunogenic neoantigens. In addition, strong expression of PD-L1 was found in the MSI CRCs relative to the CRC (MSS) stages. Localized MSI CRCs have a better prognosis than MSS CRCs, probably due to immunogenic neoantigens associated with a CD8 + T-specific immune response. On the oher hand, in metastatic CRC (mCRC) things are different because i) the MSI frequency is only 4 to 7% and ii) the good prognosis conferred by the MSI status is controversial.
Preliminary results suggest that patients with MSI mCRC are highly sensitive to ICI even chemoresistant tumors receiving several lines of chemotherapy. Recently, another anti-PD1 alone or in combination with an anti-CTLA4 (antigen associated with cytotoxic T-lymphocyte 4) was tested in the MSI CRCs and a selection of interesting results in heavily pretreated patients with a disease control rate of 56% for monotherapy and 81% for combinated therapy.
Anti-PD1s now have marketing authorization for patients with melanoma and metastatic pulmonary carcinoma , Which are known to have a high level of mutations . ICIs appear to be as promising in MSI CRCs as in other tumors and therefore face the same major challenges.
Avalumab is an anti-PD-L1 antibody recently tested in several different types of tumors with promising results and is currently being studied in phase III in gastric cancer. There is no data on the effectiveness of this ICI in the MSI mCRCs. In addition, only anti-PD1 was used in the MSI-mCRC and not the anti-PD-L1, and only in chemoresistance (3rd line or more). The main objective of the SAMCO study is to test the efficacy and tolerance of avelumab in the 2nd line of treatment in patients with a MSI mCRC progression after standard 1st line chemotherapy +/- targeted therapy.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 132
- Histologically proven colorectal adenocarcinoma with metastasis(es) non-resectable
- MSI-H determined by immunohistochemistry (loss of expression of MLH1, MSH2, MSH6 and/or PMS2) or by molecular biology
- At least one measurable target (primary tumor or metastasis) according to RECIST v1.1
- Mutational status RAS and BRAF
- Age ≥ 18
- OMS ≤ 2
- Life expectancy < 3 months
- Patient failure (progression or unacceptable toxicity) of chemotherapy containing fluoropyrimidine (capecitabine or 5FU) +/- irinotecan +/- oxaliplatin with or without cetuximab, bevacizumab and panitumumab (patients in progression during or within 3 months after discontinuation of adjuvant chemotherapy are eligible)
- PNN > 1500/mm3, platelets > 100 000/mm3, Hb > 9 g/dL
- Total bilirubin < 25 µmol/L, ASAT < 5x LSN, ALAT < 5 x LSN, PT > 60%, , PAL<2.5 x LSN ( < 5 x LSN in case of hepatic metastasis)
- Creatinine clearance > 50 ml/min according to MDRD formula (≥ 30 ml/min according to the Cockcroft-Gault formula)
- Patient belonging to a social security scheme
- Patient information and signature of the informed consent
- Patient immediately eligible for a curative therapy (surgical and/or percutaneous) after discussion in CPR
- Patient treated with FOLFIRINOX or FOLFOXIRI in 1st line
- Cerebral metastasis
- Previous treatment with anti-PD1 or anti-PDL1
- Autoimmune disease that might be aggravated during treatment with an immuno-stimulating agent (patients with type I diabetes, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible)
- Immunosuppressive long-term treatment (patients necessitating a corticotherapy are eligible if they are administered in doses < or = to the equivalent of 10 mg of prednisone daily, administration of steroids by a route resulting in minimal systemic exposure (local, intra-anal, intraocular or inhalation) are eligible).
- Transplant patients (including stem cell transplants), HIV positive or other immune deficiency syndromes
- Active infection by HBV or HCV
- Known severe hypersensitivity to monoclonal antibodies or history of anaphylactic shock, or uncontrolled asthma
- Any known specific contraindication or allergy to the treatments used in the study
- Persistence of toxicities related to 1st line chemotherapy grade > 2 (NCI-CTC v4.0) (except alopecia and neuropathy sequelae of oxaliplatin)
- Vaccination during the 4 weeks preceding the start of treatment
- Known deficit in DPD
- QT/QTc interval > 450 msec for men and > 470 msec for women
- K+ < LIN, Mg2+ < LIN, Ca2+ < LIN
- Following alterations in the 6 months prior to inclusion: myocardial infarction, angina, severe/unstable angina, coronary artery bypass surgery, congestive heart failure NYHA class II, III or IV, stroke or transient ischemic attack
- Any progressive pathology not stabilised over the past 6 months: hepatic failure, renal failure, respiratory failure
- Patient with interstitial pneumonitis or pulmonary fibrosis
- History of chronic diarrhea or inflammatory disease of the colon or rectum, or unresolved occlusion or sub-occlusion in symptomatic treatment
- History of malignant pathologies during the past 5 years except basocellular skin carcinoma or in situ cervical carcinoma, properly treated
- Patient already included in another clinical trial during treatment with an experimental molecule for L2
- Lack of effective contraception in patients (men and/or women) of childbearing age, pregnant or breastfeeding women, women of childbearing age not having had a pregnancy test
- Persons deprived of liberty or under supervision
- Impossibility of undergoing medical monitoring during the trial for geographic, social or psychological reasons
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A Chemotherapy (standard treatment) Cetuximab FOLFOX or FOLFIRI +/- targeted therapy Arm A Chemotherapy (standard treatment) FOLFOX regimen FOLFOX or FOLFIRI +/- targeted therapy Arm B - Immunotherapy (experimental arm) Avelumab Avelumab Arm A Chemotherapy (standard treatment) FOLFIRI Protocol FOLFOX or FOLFIRI +/- targeted therapy Arm A Chemotherapy (standard treatment) Panitumumab FOLFOX or FOLFIRI +/- targeted therapy Arm A Chemotherapy (standard treatment) Aflibercept FOLFOX or FOLFIRI +/- targeted therapy Arm A Chemotherapy (standard treatment) Bevacizumab FOLFOX or FOLFIRI +/- targeted therapy
- Primary Outcome Measures
Name Time Method Progression-free survival (PFS) according to the investigator up to 12 months Progression is defined as RECIST v1.1 criteria. Death is also considered as an event
- Secondary Outcome Measures
Name Time Method Overall Survival up to 60 months Defined as death due to all causes
Trial Locations
- Locations (120)
Ch - Centre Hospitalier Intercommunal
🇫🇷Villeneuve-Saint-Georges, France
Ch - Centre Hospitalier Du Pays D'Aix
🇫🇷Aix-en-Provence, France
Privé - Institut Sainte Catherine
🇫🇷Avignon CEDEX, France
Chu - Grenoble Alpes
🇫🇷Grenoble, France
Ch - Centre Hospitalier de Soisson
🇫🇷Soissons CEDEX, France
Privé - Cac - Institut de Cancérologie de Strasbourg Europe
🇫🇷Strasbourg, France
Privé - Clinique Sainte Anne
🇫🇷Strasbourg, France
Ch - Hôpital Sainte Musse
🇫🇷Toulon, France
Chu - Hôpital Trousseau
🇫🇷Tours, France
Privé - Clinique Trenel
🇫🇷Sainte-Colombe, France
Ch - Hopitaux Du Leman
🇫🇷Thonon-les-Bains, France
Chu - Hôpital Nancy-Brabois
🇫🇷Vandœuvre-lès-Nancy, France
Privé - Institut de Cancerologie de Lorraine
🇫🇷Vandœuvre-lès-Nancy, France
Chu - Aphp - Hôpital Paul Brousse
🇫🇷Villejuif, France
Privé - Cac - Gustave Roussy
🇫🇷Villejuif, France
Ch - Hopitaux Civils de Colmar
🇫🇷Colmar, France
Chu - Hôpital Rangueil
🇫🇷Toulouse, France
Privé - Centre de Radiotherapie Pierre Curie
🇫🇷Beuvry, France
Ch - Centre Hospitalier D'Abbeville
🇫🇷Abbeville CEDEX, France
Cac - Ico Site Paul Papin
🇫🇷Angers CEDEX 2, France
Privé - Hopital Privé D'Antony
🇫🇷Antony, France
Chu - Hôpital Sud - Service D'Hge
🇫🇷Amiens CEDEX 1, France
Privé - Clinique de L'Europe
🇫🇷Amiens, France
Ch - Ght Unyon Auxerre
🇫🇷Auxerre, France
CHU - Hôtel Dieu
🇫🇷Angers CEDEX 9, France
Ch - Hôpital Victor Dupouy
🇫🇷Argenteuil, France
Ch - Centre Hospitalier Ardeche Meridionale
🇫🇷Aubenas CEDEX, France
Ch - Centre Hospitalier de Beauvais
🇫🇷Beauvais, France
Ch - Centre Hôspitalier Côte Basque
🇫🇷Bayonne CEDEX, France
Ch - Hôpital Henri Duffaut
🇫🇷Avignon, France
Chu - Jean Minjoz
🇫🇷Besançon, France
Privé - Cac Institut Bergionié
🇫🇷Bordeaux, France
Privé - Polyclinique Bordeaux Nord
🇫🇷Bordeaux, France
Privé - Polyclinique Saint-Privat
🇫🇷Boujan-sur-Libron, France
Ch - Hôpital Duchenne
🇫🇷Boulogne-sur-Mer, France
Privé - Centre Maurice Tubiana
🇫🇷Caen, France
Privé - Clinique Pasteur Lanroze Cfro
🇫🇷Brest, France
Privé - Cac Centre Francois Baclesse
🇫🇷Caen, France
Privé - Infirmerie Protestante de Lyon
🇫🇷Caluire-et-Cuire, France
Ch - Centre Hospitalier William Morey
🇫🇷Chalon-sur-Saône, France
Chi - Centre Hospitalier de Castres Mazamet
🇫🇷Castres, France
Ch - Centre Hospitalier Metropole Savoie
🇫🇷Chambéry CEDEX, France
Ch - Centre Hospitalier de Carcassonne
🇫🇷Carcassonne, France
Privé - Hopital Prive Sainte Marie
🇫🇷Chalon-sur-Saône, France
Privé - Clinique de Flandre
🇫🇷Coudekerque-Branche, France
Ch - Centre Hospitalier de Châteauroux
🇫🇷Châteauroux, France
Ch - Centre Hospitalier de Charleville Mezieres
🇫🇷Charleville, France
Ch - Centre Hospitalier de Cholet
🇫🇷Cholet, France
Ch - Centre Hospitalier General
🇫🇷Châlons-en-Champagne, France
Privé - Clinique Saint Come
🇫🇷Compiègne CEDEX, France
Ch - Centre Hospitalier Sud Francilien
🇫🇷Corbeil-Essonnes, France
Privé - Clinique Des Cèdres
🇫🇷Cornebarrieu, France
Chu - Aphp - Hopital Henri Mondor
🇫🇷Créteil CEDEX, France
Ch - Ghpso Site de Creil
🇫🇷Creil, France
Ch - Chic de Créteil
🇫🇷Créteil, France
Chu - Hopital Francois Mitterrand
🇫🇷Dijon CEDEX, France
Privé - Institut de Cancerologie de Bourgogne Grrecc
🇫🇷Dijon, France
Privé - Cac- Centre Georges-Francois Leclerc
🇫🇷Dijon, France
Privé - Ghm Institut Daniel Hollard
🇫🇷Grenoble, France
Ch - Centre Hospitalier Docteur Schaffner
🇫🇷Lens, France
Privé - Clinique Sainte Marguerite
🇫🇷Hyères, France
Ch - Centre Hospitalier Marne La Vallee-Jossigny
🇫🇷Jossigny, France
Chd - Centre Hospitalier Vendee
🇫🇷La Roche-sur-Yon, France
Privé - Clinique Du Cap D'Or
🇫🇷La Seyne-sur-Mer, France
Ch - Hopital Louis Pasteur - Oncologie Hematologie
🇫🇷Le Coudray, France
Ch - Hopital Andre Mignot
🇫🇷Le Chesnay, France
Privé - Cmc Les Ormeaux
🇫🇷Le Havre, France
Chu - Aphp - Hôpital de Bicêtre
🇫🇷Le Kremlin-Bicêtre, France
Ch - Centre Hospitalier Du Mans
🇫🇷Le Mans CEDEX 9, France
Ch - Hôpital Franco Britannique
🇫🇷Levallois-Perret, France
Privé - Cac - Centre Oscar Lambret
🇫🇷Lille, France
Chu - Hôpital de La Croix Rousse
🇫🇷Lyon, France
Chu - Dupuytren
🇫🇷Limoges, France
Chu - Hôpital Edouard Herriot
🇫🇷Lyon, France
Ch - Gh Nord Essone
🇫🇷Longjumeau, France
Privé - Hôpital Européen Marseille
🇫🇷Marseille CEDEX 03, France
Privé - Cac Centre Léon Berard
🇫🇷Lyon, France
Privé - Cac Institut Paoli Calmettes
🇫🇷Marseille CEDEX 9, France
Chu - La Timone
🇫🇷Marseille CEDEX 5, France
Ch - Hôpital Saint Joseph
🇫🇷Marseille, France
Ch - Ghi de L'Est Francilien Site de Meaux
🇫🇷Meaux, France
Privé - Clinique Claude Bernard
🇫🇷Metz, France
Ch - Hôpital Layné
🇫🇷Mont-de-Marsan, France
Ch - Hôpital Belle Isle
🇫🇷Metz, France
Ch - Centre Hospitalier de Montceau Les Mines
🇫🇷Montceau-les-Mines, France
Ch - Groupe Hospitalier Intercommunal Le Raincy
🇫🇷Montfermeil, France
Privé - Hôpital Prive Du Confluent Sas
🇫🇷Nantes, France
Privé - Centre de Cancérologie Du Grand Montpellier
🇫🇷Montpellier, France
Ch - Centre Hospitalier de Montélimar
🇫🇷Montélimar, France
Chr - Centre Hospitalier Régional de La Source
🇫🇷Orléans, France
Chu - Hôpital Caremeau
🇫🇷Nîmes, France
Privé - Cac - Centre Antoine Lacassagne
🇫🇷Nice, France
Privé - Cac - Institut Curie
🇫🇷Paris, France
Chu - Hôpital Cochin
🇫🇷Paris, France
Chu - Hôpital Europeen Georges Pompidou
🇫🇷Paris, France
Chu - Aphp - Hôpital Saint Louis
🇫🇷Paris, France
Chu - Aphp - Gh La Pitié Salpêtrière
🇫🇷Paris, France
Chu - Hôpital Saint Antoine
🇫🇷Paris, France
Ch - Centre Hospitalier de Pau
🇫🇷Pau CEDEX, France
Ch - Hôpital Saint Jean
🇫🇷Perpignan, France
Ch - Hôpital Lyon Sud
🇫🇷Pierre-Bénite, France
Chu - Hôpital Haut Lévêque
🇫🇷Pessac CEDEX, France
Ch - Hôpital Rene Dubos
🇫🇷Pontoise, France
Privé - Centre Cario - Hcpa
🇫🇷Plérin, France
Chu - Hôpital de La Miletrie
🇫🇷Poitiers, France
Privé - Polyclinique Francheville
🇫🇷Périgueux, France
Ch - Hôpital Annecy Genevois
🇫🇷Pringy, France
Ch - Chic - Centre Hospitalier de Cornouaille
🇫🇷Quimper, France
Chu - Hôpital Robert Debre
🇫🇷Reims CEDEX, France
Chu - Centre Hospitalier Universitaire Pontchaillou
🇫🇷Rennes, France
Privé - Centre de Radiotherapie Et D'Oncologie Médicale de L'Essone
🇫🇷Ris-Orangis, France
Privé - Clinique Pasteur
🇫🇷Ris-Orangis, France
Chu - Hôpital Charles Nicolle
🇫🇷Rouen CEDEX 01, France
Privé - Clinique Mutualiste de L'Estuaire - Cite Sanitaire
🇫🇷Saint Nazaire, France
Ch - Hôpitaux Drome Nord
🇫🇷Romans-sur-Isère, France
Privé - Clinique de L'Union
🇫🇷Saint-Jean, France
Ch - Centre Hospitalier de Saint-Malo
🇫🇷Saint-Malo, France
Privé - Hôpital Privé Saint Gregoire
🇫🇷Saint-Grégoire, France
Privé - Cmco Côte D'Opale
🇫🇷Saint-Martin-Boulogne, France
Chu - Hôpital Nord - Saint-Étienne
🇫🇷Saint-Priest-en-Jarez, France