Clinical trial NCT03186326: Standard Chemotherapy vs Immunotherapie in 2nd Line Treatment of MSI Colorectal Mestastatic Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
MSI
Keywords: immunotherapy
second line
Lead sponsor: Federation Francophone de Cancerologie Digestive
Sponsor class: OTHER
First posted: 2017-06-14
Enrollment: 132
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Progression-free survival (PFS) according to the investigator
timeFrame: up to 12 months
Secondary outcomes:
measure: Overall Survival
timeFrame: up to 60 months
Other outcomes:
Locations:
city: Abbeville CEDEX
country: France
facility: Ch - Centre Hospitalier D'Abbeville
city: Aix-en-Provence
country: France
facility: Ch - Centre Hospitalier Du Pays D'Aix
city: Amiens CEDEX 1
country: France
facility: Chu - Hôpital Sud - Service D'Hge
city: Amiens
country: France
facility: Privé - Clinique de L'Europe
city: Angers CEDEX 2
country: France
facility: Cac - Ico Site Paul Papin
city: Angers CEDEX 9
country: France
facility: CHU - Hôtel Dieu
city: Antony
country: France
facility: Privé - Hopital Privé D'Antony
city: Argenteuil
country: France
facility: Ch - Hôpital Victor Dupouy
city: Aubenas CEDEX
country: France
facility: Ch - Centre Hospitalier Ardeche Meridionale
city: Auxerre
country: France
facility: Ch - Ght Unyon Auxerre
city: Avignon CEDEX
country: France
facility: Privé - Institut Sainte Catherine
city: Avignon
country: France
facility: Ch - Hôpital Henri Duffaut
city: Bayonne CEDEX
country: France
facility: Ch - Centre Hôspitalier Côte Basque
city: Beauvais
country: France
facility: Ch - Centre Hospitalier de Beauvais
city: Besançon
country: France
facility: Chu - Jean Minjoz
city: Beuvry
country: France
facility: Privé - Centre de Radiotherapie Pierre Curie
city: Bordeaux
country: France
facility: Privé - Polyclinique Bordeaux Nord
city: Bordeaux
country: France
facility: Privé - Cac Institut Bergionié
city: Boujan-sur-Libron
country: France
facility: Privé - Polyclinique Saint-Privat
city: Boulogne-sur-Mer
country: France
facility: Ch - Hôpital Duchenne
city: Brest
country: France
facility: Privé - Clinique Pasteur Lanroze Cfro
city: Caen
country: France
facility: Privé - Centre Maurice Tubiana
city: Caen
country: France
facility: Privé - Cac Centre Francois Baclesse
city: Caluire-et-Cuire
country: France
facility: Privé - Infirmerie Protestante de Lyon
city: Carcassonne
country: France
facility: Ch - Centre Hospitalier de Carcassonne
city: Castres
country: France
facility: Chi - Centre Hospitalier de Castres Mazamet
city: Chalon-sur-Saône
country: France
facility: Ch - Centre Hospitalier William Morey
city: Chalon-sur-Saône
country: France
facility: Privé - Hopital Prive Sainte Marie
city: Chambéry CEDEX
country: France
facility: Ch - Centre Hospitalier Metropole Savoie
city: Charleville
country: France
facility: Ch - Centre Hospitalier de Charleville Mezieres
city: Cholet
country: France
facility: Ch - Centre Hospitalier de Cholet
city: Châlons-en-Champagne
country: France
facility: Ch - Centre Hospitalier General
city: Châteauroux
country: France
facility: Ch - Centre Hospitalier de Châteauroux
city: Colmar
country: France
facility: Ch - Hopitaux Civils de Colmar
city: Compiègne CEDEX
country: France
facility: Privé - Clinique Saint Come
city: Corbeil-Essonnes
country: France
facility: Ch - Centre Hospitalier Sud Francilien
city: Cornebarrieu
country: France
facility: Privé - Clinique Des Cèdres
city: Coudekerque-Branche
country: France
facility: Privé - Clinique de Flandre
city: Creil
country: France
facility: Ch - Ghpso Site de Creil
city: Créteil CEDEX
country: France
facility: Chu - Aphp - Hopital Henri Mondor
city: Créteil
country: France
facility: Ch - Chic de Créteil
city: Dijon CEDEX
country: France
facility: Chu - Hopital Francois Mitterrand
city: Dijon
country: France
facility: Privé - Institut de Cancerologie de Bourgogne Grrecc
city: Dijon
country: France
facility: Privé - Cac- Centre Georges-Francois Leclerc
city: Grenoble
country: France
facility: Privé - Ghm Institut Daniel Hollard
city: Grenoble
country: France
facility: Chu - Grenoble Alpes
city: Hyères
country: France
facility: Privé - Clinique Sainte Marguerite
city: Jossigny
country: France
facility: Ch - Centre Hospitalier Marne La Vallee-Jossigny
city: La Roche-sur-Yon
country: France
facility: Chd - Centre Hospitalier Vendee
city: La Seyne-sur-Mer
country: France
facility: Privé - Clinique Du Cap D'Or
city: Le Chesnay
country: France
facility: Ch - Hopital Andre Mignot
city: Le Coudray
country: France
facility: Ch - Hopital Louis Pasteur - Oncologie Hematologie
city: Le Havre
country: France
facility: Privé - Cmc Les Ormeaux
city: Le Kremlin-Bicêtre
country: France
facility: Chu - Aphp - Hôpital de Bicêtre
city: Le Mans CEDEX 9
country: France
facility: Ch - Centre Hospitalier Du Mans
city: Lens
country: France
facility: Ch - Centre Hospitalier Docteur Schaffner
city: Levallois-Perret
country: France
facility: Ch - Hôpital Franco Britannique
city: Lille
country: France
facility: Privé - Cac - Centre Oscar Lambret
city: Limoges
country: France
facility: Chu - Dupuytren
city: Longjumeau
country: France
facility: Ch - Gh Nord Essone
city: Lyon
country: France
facility: Chu - Hôpital de La Croix Rousse
city: Lyon
country: France
facility: Privé - Cac Centre Léon Berard
city: Lyon
country: France
facility: Chu - Hôpital Edouard Herriot
city: Marseille CEDEX 03
country: France
facility: Privé - Hôpital Européen Marseille
city: Marseille CEDEX 5
country: France
facility: Chu - La Timone
city: Marseille CEDEX 9
country: France
facility: Privé - Cac Institut Paoli Calmettes
city: Marseille
country: France
facility: Ch - Hôpital Saint Joseph
city: Meaux
country: France
facility: Ch - Ghi de L'Est Francilien Site de Meaux
city: Metz
country: France
facility: Ch - Hôpital Belle Isle
city: Metz
country: France
facility: Privé - Clinique Claude Bernard
city: Mont-de-Marsan
country: France
facility: Ch - Hôpital Layné
city: Montceau-les-Mines
country: France
facility: Ch - Centre Hospitalier de Montceau Les Mines
city: Montfermeil
country: France
facility: Ch - Groupe Hospitalier Intercommunal Le Raincy
city: Montpellier
country: France
facility: Privé - Centre de Cancérologie Du Grand Montpellier
city: Montélimar
country: France
facility: Ch - Centre Hospitalier de Montélimar
city: Nantes
country: France
facility: Privé - Hôpital Prive Du Confluent Sas
city: Nice
country: France
facility: Privé - Cac - Centre Antoine Lacassagne
city: Nîmes
country: France
facility: Chu - Hôpital Caremeau
city: Orléans
country: France
facility: Chr - Centre Hospitalier Régional de La Source
city: Paris
country: France
facility: Privé - Cac - Institut Curie
city: Paris
country: France
facility: Chu - Hôpital Cochin
city: Paris
country: France
facility: Chu - Hôpital Europeen Georges Pompidou
city: Paris
country: France
facility: Chu - Aphp - Hôpital Saint Louis
city: Paris
country: France
facility: Chu - Hôpital Saint Antoine
city: Paris
country: France
facility: Chu - Aphp - Gh La Pitié Salpêtrière
city: Pau CEDEX
country: France
facility: Ch - Centre Hospitalier de Pau
city: Perpignan
country: France
facility: Ch - Hôpital Saint Jean
city: Pessac CEDEX
country: France
facility: Chu - Hôpital Haut Lévêque
city: Pierre-Bénite
country: France
facility: Ch - Hôpital Lyon Sud
city: Plérin
country: France
facility: Privé - Centre Cario - Hcpa
city: Poitiers
country: France
facility: Chu - Hôpital de La Miletrie
city: Pontoise
country: France
facility: Ch - Hôpital Rene Dubos
city: Pringy
country: France
facility: Ch - Hôpital Annecy Genevois
city: Périgueux
country: France
facility: Privé - Polyclinique Francheville
city: Quimper
country: France
facility: Ch - Chic - Centre Hospitalier de Cornouaille
city: Reims CEDEX
country: France
facility: Chu - Hôpital Robert Debre
city: Rennes
country: France
facility: Chu - Centre Hospitalier Universitaire Pontchaillou
city: Ris-Orangis
country: France
facility: Privé - Centre de Radiotherapie Et D'Oncologie Médicale de L'Essone
city: Ris-Orangis
country: France
facility: Privé - Clinique Pasteur
city: Romans-sur-Isère
country: France
facility: Ch - Hôpitaux Drome Nord
city: Rouen CEDEX 01
country: France
facility: Chu - Hôpital Charles Nicolle
city: Saint Nazaire
country: France
facility: Privé - Clinique Mutualiste de L'Estuaire - Cite Sanitaire
city: Saint-Grégoire
country: France
facility: Privé - Hôpital Privé Saint Gregoire
city: Saint-Jean
country: France
facility: Privé - Clinique de L'Union
city: Saint-Malo
country: France
facility: Ch - Centre Hospitalier de Saint-Malo
city: Saint-Martin-Boulogne
country: France
facility: Privé - Cmco Côte D'Opale
city: Saint-Priest-en-Jarez
country: France
facility: Chu - Hôpital Nord - Saint-Étienne
city: Sainte-Colombe
country: France
facility: Privé - Clinique Trenel
city: Soissons CEDEX
country: France
facility: Ch - Centre Hospitalier de Soisson
city: Strasbourg
country: France
facility: Privé - Cac - Institut de Cancérologie de Strasbourg Europe
city: Strasbourg
country: France
facility: Privé - Clinique Sainte Anne
city: Thonon-les-Bains
country: France
facility: Ch - Hopitaux Du Leman
city: Toulon
country: France
facility: Ch - Hôpital Sainte Musse
city: Toulouse
country: France
facility: Chu - Hôpital Rangueil
city: Tours
country: France
facility: Chu - Hôpital Trousseau
city: Vandœuvre-lès-Nancy
country: France
facility: Chu - Hôpital Nancy-Brabois
city: Vandœuvre-lès-Nancy
country: France
facility: Privé - Institut de Cancerologie de Lorraine
city: Villejuif
country: France
facility: Chu - Aphp - Hôpital Paul Brousse
city: Villejuif
country: France
facility: Privé - Cac - Gustave Roussy
city: Villeneuve-Saint-Georges
country: France
facility: Ch - Centre Hospitalier Intercommunal
Study officials:
affiliation: HOPITAL EUROPEEN G. POMPIDOU
name: Julien Taieb, Pr
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.