Standard Chemotherapy vs Immunotherapie in 2nd Line Treatment of MSI Colorectal Mestastatic Cancer (SAMCO)

Multicenter Randomized Phase II Study Comparing the Effectiveness and Tolerance of Avelumab Versus Standard 2nd Line Treatment Chemotherapy in Patients With Colorectal Metastatic Cancer With Microsatellite Instability (MSI)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Colorectal Cancer; MSI
• Intervention / Treatment: Drug: FOLFOX regimen; Drug: FOLFIRI Protocol; Drug: Panitumumab; Drug: Cetuximab; Drug: Bevacizumab; Drug: Aflibercept; Drug: Avelumab

• Study Type: Interventional
• Enrollment (Actual): 132
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Abbeville CEDEX, France, 80142
    • Ch - Centre Hospitalier D'Abbeville
  • Aix-en-Provence, France, 13616
    • Ch - Centre Hospitalier Du Pays D'Aix
  • Amiens, France, 80090
    • Privé - Clinique de L'Europe
  • Amiens CEDEX 1, France, 80054
    • Chu - Hôpital Sud - Service D'Hge
  • Angers CEDEX 2, France, 49055
    • CAC - ICO Site Paul Papin
  • Angers CEDEX 9, France, 49933
    • CHU - Hôtel Dieu
  • Antony, France, 92166
    • Privé - Hôpital Privé D'Antony
  • Argenteuil, France, 95100
    • Ch - Hôpital Victor Dupouy
  • Aubenas CEDEX, France, 07205
    • Ch - Centre Hospitalier Ardeche Meridionale
  • Auxerre, France, 89000
    • Ch - Ght Unyon Auxerre
  • Avignon, France, 84000
    • Ch - Hôpital Henri Duffaut
  • Avignon CEDEX, France, 84918
    • Privé - Institut Sainte Catherine
  • Bayonne CEDEX, France, 64109
    • Ch - Centre Hôspitalier Côte Basque
  • Beauvais, France, 60021
    • Ch - Centre Hospitalier de Beauvais
  • Besançon, France, 25030
    • Chu - Jean Minjoz
  • Beuvry, France, 62660
    • Privé - Centre de Radiotherapie Pierre Curie
  • Bordeaux, France, 33000
    • PRIVE - Polyclinique Bordeaux Nord
  • Bordeaux, France, 33076
    • Privé - Cac Institut Bergionié
  • Boujan-sur-Libron, France, 34760
    • Privé - Polyclinique Saint-Privat
  • Boulogne-sur-Mer, France, 62321
    • Ch - Hôpital Duchenne
  • Brest, France, 29200
    • Privé - Clinique Pasteur Lanroze Cfro
  • Caen, France, 14052
    • Privé - Centre Maurice Tubiana
  • Caen, France, 14076
    • Privé - Cac Centre Francois Baclesse
  • Caluire-et-Cuire, France, 69300
    • PRIVE - Infirmerie Protestante de Lyon
  • Carcassonne, France, 11000
    • Ch - Centre Hospitalier de Carcassonne
  • Castres, France, 81090
    • Chi - Centre Hospitalier de Castres Mazamet
  • Chalon-sur-Saône, France, 7100
    • Ch - Centre Hospitalier William Morey
  • Chalon-sur-Saône, France, 71100
    • Privé - Hopital Prive Sainte Marie
  • Chambéry CEDEX, France, 73011
    • Ch - Centre Hospitalier Metropole Savoie
  • Charleville, France, 08000
    • Ch - Centre Hospitalier de Charleville Mezieres
  • Cholet, France, 49300
    • Ch - Centre Hospitalier de Cholet
  • Châlons-en-Champagne, France, 51005
    • Ch - Centre Hospitalier General
  • Châteauroux, France, 36000
    • Ch - Centre Hospitalier de Châteauroux
  • Colmar, France, 68024
    • Ch - Hôpitaux Civils de Colmar
  • Compiègne CEDEX, France, 60204
    • Privé - Clinique Saint Come
  • Corbeil-Essonnes, France, 91106
    • Ch - Centre Hospitalier Sud Francilien
  • Cornebarrieu, France, 31700
    • Privé - Clinique Des Cèdres
  • Coudekerque-Branche, France, 59210
    • Privé - Clinique de Flandre
  • Creil, France, 60100
    • CH - GHPSO Site de Creil
  • Créteil, France, 94000
    • Ch - Chic de Créteil
  • Créteil CEDEX, France, 94000
    • Chu - Aphp - Hopital Henri Mondor
  • Dijon, France, 21000
    • PRIVE - Institut de Cancérologie de Bourgogne GRReCC
  • Dijon, France, 21079
    • Privé - Cac- Centre Georges-Francois Leclerc
  • Dijon CEDEX, France, 21079
    • Chu - Hôpital François Mitterrand
  • Grenoble, France, 38028
    • Privé - Ghm Institut Daniel Hollard
  • Grenoble, France
    • CHU - Grenoble Alpes
  • Hyères, France, 83400
    • Privé - Clinique Sainte Marguerite
  • Jossigny, France, 77600
    • Ch - Centre Hospitalier Marne La Vallee-Jossigny
  • La Roche-sur-Yon, France, 85925
    • Chd - Centre Hospitalier Vendee
  • La Seyne-sur-Mer, France, 83500
    • Privé - Clinique Du Cap D'Or
  • Le Chesnay, France, 78157
    • Ch - Hopital Andre Mignot
  • Le Coudray, France, 28630
    • Ch - Hopital Louis Pasteur - Oncologie Hematologie
  • Le Havre, France, 76600
    • Privé - Cmc Les Ormeaux
  • Le Kremlin-Bicêtre, France, 94270
    • Chu - Aphp - Hôpital de Bicêtre
  • Le Mans CEDEX 9, France, 72037
    • Ch - Centre Hospitalier Du Mans
  • Lens, France
    • Ch - Centre Hospitalier Docteur Schaffner
  • Levallois-Perret, France, 92300
    • Ch - Hôpital Franco Britannique
  • Lille, France, 59000
    • Privé - Cac - Centre Oscar Lambret
  • Limoges, France, 87042
    • Chu - Dupuytren
  • Longjumeau, France, 91160
    • CH - GH Nord Essone
  • Lyon, France, 69317
    • Chu - Hôpital de La Croix Rousse
  • Lyon, France, 69373
    • Privé - Cac Centre Léon Berard
  • Lyon, France, 69437
    • Chu - Hôpital Edouard Herriot
  • Marseille, France, 13285
    • Ch - Hôpital Saint Joseph
  • Marseille CEDEX 03, France, 13331
    • Privé - Hôpital Européen Marseille
  • Marseille CEDEX 5, France, 13385
    • CHU - La Timone
  • Marseille CEDEX 9, France, 13273
    • Privé - Cac Institut Paoli Calmettes
  • Meaux, France, 77100
    • CH - GHI de l'Est Francilien Site de Meaux
  • Metz, France, 57000
    • Ch - Hôpital Belle Isle
  • Metz, France, 57070
    • PRIVE - Clinique Claude Bernard
  • Mont-de-Marsan, France, 40024
    • Ch - Hôpital Layné
  • Montceau-les-Mines, France, 71300
    • Ch - Centre Hospitalier de Montceau Les Mines
  • Montfermeil, France, 93370
    • Ch - Groupe Hospitalier Intercommunal Le Raincy
  • Montpellier, France, 34070
    • Privé - Centre de Cancérologie Du Grand Montpellier
  • Montélimar, France, 26216
    • Ch - Centre Hospitalier de Montélimar
  • Nantes, France, 44577
    • Privé - Hôpital Prive Du Confluent Sas
  • Nice, France, 06000
    • Privé - Cac - Centre Antoine Lacassagne
  • Nîmes, France, 30000
    • Chu - Hôpital Carémeau
  • Orléans, France, 45067
    • Chr - Centre Hospitalier Régional de La Source
  • Paris, France, 75005
    • Privé - Cac - Institut Curie
  • Paris, France, 75014
    • Chu - Hôpital Cochin
  • Paris, France, 75015
    • Chu - Hôpital Européen Georges Pompidou
  • Paris, France, 75475
    • Chu - Aphp - Hôpital Saint Louis
  • Paris, France, 75571
    • Chu - Hôpital Saint Antoine
  • Paris, France, 75651
    • Chu - Aphp - Gh La Pitié Salpêtrière
  • Pau CEDEX, France, 64046
    • CH - Centre Hospitalier de Pau
  • Perpignan, France, 66046
    • Ch - Hôpital Saint Jean
  • Pessac CEDEX, France, 33604
    • Chu - Hôpital Haut Lévêque
  • Pierre-Bénite, France, 69310
    • Ch - Hôpital Lyon Sud
  • Plérin, France, 22190
    • Privé - Centre Cario - Hcpa
  • Poitiers, France, 86021
    • CHU - Hôpital de la Milétrie
  • Pontoise, France, 95300
    • Ch - Hôpital Rene Dubos
  • Pringy, France, 74374
    • Ch - Hôpital Annecy Genevois
  • Périgueux, France, 24000
    • Privé - Polyclinique Francheville
  • Quimper, France, 29000
    • Ch - Chic - Centre Hospitalier de Cornouaille
  • Reims CEDEX, France, 51092
    • CHU - Hôpital Robert Debré
  • Rennes, France, 35000
    • Chu - Centre Hospitalier Universitaire Pontchaillou
  • Ris-Orangis, France, 91130
    • Privé - Centre de Radiotherapie Et D'Oncologie Médicale de L'Essone
  • Ris-Orangis, France, 91130
    • Privé - Clinique Pasteur
  • Romans-sur-Isère, France, 26100
    • Ch - Hôpitaux Drome Nord
  • Rouen CEDEX 01, France, 76031
    • Chu - Hôpital Charles Nicolle
  • Saint Nazaire, France, 44600
    • Privé - Clinique Mutualiste de L'Estuaire - Cite Sanitaire
  • Saint-Grégoire, France, 35768
    • Privé - Hôpital Privé Saint Gregoire
  • Saint-Jean, France, 31240
    • Privé - Clinique de L'Union
  • Saint-Malo, France, 35400
    • Ch - Centre Hospitalier de Saint-Malo
  • Saint-Martin-Boulogne, France, 62280
    • Privé - Cmco Côte D'Opale
  • Saint-Priest-en-Jarez, France, 42270
    • CHU - Hôpital Nord - Saint-Étienne
  • Sainte-Colombe, France
    • Privé - Clinique Trenel
  • Soissons CEDEX, France, 02209
    • Ch - Centre Hospitalier de Soisson
  • Strasbourg, France
    • Privé - Cac - Institut de Cancérologie de Strasbourg Europe
  • Strasbourg, France
    • Privé - Clinique Sainte Anne
  • Thonon-les-Bains, France, 74203
    • Ch - Hopitaux Du Leman
  • Toulon, France, 83000
    • Ch - Hôpital Sainte Musse
  • Toulouse, France, 31000
    • Chu - Hôpital Rangueil
  • Tours, France, 37044
    • Chu - Hôpital Trousseau
  • Vandœuvre-lès-Nancy, France, 54511
    • Chu - Hôpital Nancy-Brabois
  • Vandœuvre-lès-Nancy, France, 54519
    • Privé - Institut de Cancerologie de Lorraine
  • Villejuif, France, 94800
    • Chu - Aphp - Hôpital Paul Brousse
  • Villejuif, France
    • Privé - Cac - Gustave Roussy
  • Villeneuve-Saint-Georges, France, 94190
    • Ch - Centre Hospitalier Intercommunal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A Chemotherapy (standard treatment); FOLFOX or FOLFIRI +/- targeted therapy	Drug: FOLFOX regimen; A course of treatment every 14 days Oxaliplatin: 85 mg/m² IV over 2 hours Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine) IV over 2 hours 5FU bolus: 400 mg/m² IV bolus over 10 minutes in 100 ml 0.9% NaCl 5FU continuous: 2,400 mg/m² in NaCl 0.9% in IV over 46 hours; Drug: FOLFIRI Protocol; A course of treatment every 14 days Irinotecan: 180 mg/m² IV over 1H30 Folinic acid: 400 mg/m² (or 200 mg/m² if Elvorine) IV over 2 hours 5FU bolus: 400 mg/m² IV bolus over 10 minutes in 100 ml 0.9% NaCl 5FU continuous: 2,400 mg/m² in NaCl 0.9% in IV over 46 hours; Drug: Panitumumab; Administered at 6 mg/Kg; Drug: Cetuximab; Administered at 500 mg/m²; Drug: Bevacizumab; Administered at 5 mg/Kg; Drug: Aflibercept; Administered at 4 mg/Kg
Experimental: Arm B - Immunotherapy (experimental arm); Avelumab	Drug: Avelumab; A course of treatment every 14 days. Premedication obligatory with antihistamines and paracetamol (example: 25-50 mg diphenhydramine and 500-650 mg paracetamol) IV, approximately 30 to 60 minutes before each dose of avelumab. Then: Avelumab: 10 mg/kg IV in 1 hour diluted with 0.9% saline solution; alternatively a 0.45% saline solution can be used if needed

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) according to the investigator	Progression is defined as RECIST v1.1 criteria. Death is also considered as an event	up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Defined as death due to all causes	up to 60 months

Collaborators and Investigators

• Sponsor: Federation Francophone de Cancerologie Digestive
• Investigators: Principal Investigator: Julien Taieb, Pr, Hopital Europeen G. Pompidou

Publications and helpful links

General Publications

• Taieb J, Andre T, El Hajbi F, Barbier E, Toullec C, Kim S, Bouche O, Di Fiore F, Chauvenet M, Perrier H, Evesque L, Laurent-Puig P, Emile JF, Bez J, Lepage C, Tougeron D. Avelumab versus standard second line treatment chemotherapy in metastatic colorectal cancer patients with microsatellite instability: The SAMCO-PRODIGE 54 randomised phase II trial. Dig Liver Dis. 2021 Mar;53(3):318-323. doi: 10.1016/j.dld.2020.11.031. Epub 2020 Dec 25.

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2018
• Primary Completion (Actual): May 31, 2022
• Study Completion (Anticipated): May 31, 2023

Study Registration Dates

• First Submitted: May 17, 2017
• First Submitted That Met QC Criteria: June 13, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Actual): August 19, 2022
• Last Update Submitted That Met QC Criteria: August 18, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: immunotherapy; second line
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab; Avelumab; Panitumumab; Cetuximab; Aflibercept
• Other Study ID Numbers: PRODIGE 54 - FFCD 1603

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No