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

Metastatic Colorectal Cancer Clinical Trial

— SAMCO  

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03186326
• Other study ID #: PRODIGE 54 - FFCD 1603
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 24, 2018
• Est. completion date: May 31, 2023

Study information

• Verified date: August 2022
• Source: Federation Francophone de Cancerologie Digestive
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 132
• Est. completion date: May 31, 2023
• Est. primary completion date: May 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer
• MSI

Intervention

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
• 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
• 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
• Panitumumab
Administered at 6 mg/Kg
• Cetuximab
Administered at 500 mg/m²
• Bevacizumab
Administered at 5 mg/Kg
• Aflibercept
Administered at 4 mg/Kg

Locations

Country	Name	City	State
France	Ch - Centre Hospitalier D'Abbeville	Abbeville CEDEX
France	Ch - Centre Hospitalier Du Pays D'Aix	Aix-en-Provence
France	Privé - Clinique de L'Europe	Amiens
France	Chu - Hôpital Sud - Service D'Hge	Amiens CEDEX 1
France	Cac - Ico Site Paul Papin	Angers CEDEX 2
France	CHU - Hôtel Dieu	Angers CEDEX 9
France	Privé - Hopital Privé D'Antony	Antony
France	Ch - Hôpital Victor Dupouy	Argenteuil
France	Ch - Centre Hospitalier Ardeche Meridionale	Aubenas CEDEX
France	Ch - Ght Unyon Auxerre	Auxerre
France	Ch - Hôpital Henri Duffaut	Avignon
France	Privé - Institut Sainte Catherine	Avignon CEDEX
France	Ch - Centre Hôspitalier Côte Basque	Bayonne CEDEX
France	Ch - Centre Hospitalier de Beauvais	Beauvais
France	Chu - Jean Minjoz	Besançon
France	Privé - Centre de Radiotherapie Pierre Curie	Beuvry
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 - Clinique Pasteur Lanroze Cfro	Brest
France	Privé - Cac Centre Francois Baclesse	Caen
France	Privé - Centre Maurice Tubiana	Caen
France	Privé - Infirmerie Protestante de Lyon	Caluire-et-Cuire
France	Ch - Centre Hospitalier de Carcassonne	Carcassonne
France	Chi - Centre Hospitalier de Castres Mazamet	Castres
France	Ch - Centre Hospitalier William Morey	Chalon-sur-Saône
France	Privé - Hopital Prive Sainte Marie	Chalon-sur-Saône
France	Ch - Centre Hospitalier General	Châlons-en-Champagne
France	Ch - Centre Hospitalier Metropole Savoie	Chambéry CEDEX
France	Ch - Centre Hospitalier de Charleville Mezieres	Charleville
France	Ch - Centre Hospitalier de Châteauroux	Châteauroux
France	Ch - Centre Hospitalier de Cholet	Cholet
France	Ch - Hopitaux Civils de Colmar	Colmar
France	Privé - Clinique Saint Come	Compiègne CEDEX
France	Ch - Centre Hospitalier Sud Francilien	Corbeil-Essonnes
France	Privé - Clinique Des Cèdres	Cornebarrieu
France	Privé - Clinique de Flandre	Coudekerque-Branche
France	Ch - Ghpso Site de Creil	Creil
France	Ch - Chic de Créteil	Créteil
France	Chu - Aphp - Hopital Henri Mondor	Créteil CEDEX
France	Privé - Cac- Centre Georges-Francois Leclerc	Dijon
France	Privé - Institut de Cancerologie de Bourgogne Grrecc	Dijon
France	Chu - Hopital Francois Mitterrand	Dijon CEDEX
France	Chu - Grenoble Alpes	Grenoble
France	Privé - Ghm Institut Daniel Hollard	Grenoble
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 Andre Mignot	Le Chesnay
France	Ch - Hopital Louis Pasteur - Oncologie Hematologie	Le Coudray
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 - Centre Hospitalier Docteur Schaffner	Lens
France	Ch - Hôpital Franco Britannique	Levallois-Perret
France	Privé - Cac - Centre Oscar Lambret	Lille
France	Chu - Dupuytren	Limoges
France	Ch - Gh Nord Essone	Longjumeau
France	Chu - Hôpital de La Croix Rousse	Lyon
France	Chu - Hôpital Edouard Herriot	Lyon
France	Privé - Cac Centre Léon Berard	Lyon
France	Ch - Hôpital Saint Joseph	Marseille
France	Privé - Hôpital Européen Marseille	Marseille CEDEX 03
France	Chu - La Timone	Marseille CEDEX 5
France	Privé - Cac Institut Paoli Calmettes	Marseille CEDEX 9
France	Ch - Ghi de L'Est Francilien Site de Meaux	Meaux
France	Ch - Hôpital Belle Isle	Metz
France	Privé - Clinique Claude Bernard	Metz
France	Ch - Hôpital Layné	Mont-de-Marsan
France	Ch - Centre Hospitalier de Montceau Les Mines	Montceau-les-Mines
France	Ch - Centre Hospitalier de Montélimar	Montélimar
France	Ch - Groupe Hospitalier Intercommunal Le Raincy	Montfermeil
France	Privé - Centre de Cancérologie Du Grand Montpellier	Montpellier
France	Privé - Hôpital Prive Du Confluent Sas	Nantes
France	Privé - Cac - Centre Antoine Lacassagne	Nice
France	Chu - Hôpital Caremeau	Nîmes
France	Chr - Centre Hospitalier Régional de La Source	Orléans
France	Chu - Aphp - Gh La Pitié Salpêtrière	Paris
France	Chu - Aphp - Hôpital Saint Louis	Paris
France	Chu - Hôpital Cochin	Paris
France	Chu - Hôpital Europeen Georges Pompidou	Paris
France	Chu - Hôpital Saint Antoine	Paris
France	Privé - Cac - Institut Curie	Paris
France	Ch - Centre Hospitalier de Pau	Pau CEDEX
France	Privé - Polyclinique Francheville	Périgueux
France	Ch - Hôpital Saint Jean	Perpignan
France	Chu - Hôpital Haut Lévêque	Pessac CEDEX
France	Ch - Hôpital Lyon Sud	Pierre-Bénite
France	Privé - Centre Cario - Hcpa	Plérin
France	Chu - Hôpital de La Miletrie	Poitiers
France	Ch - Hôpital Rene Dubos	Pontoise
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	Ch - Hôpitaux Drome Nord	Romans-sur-Isère
France	Chu - Hôpital Charles Nicolle	Rouen CEDEX 01
France	Privé - Clinique Mutualiste de L'Estuaire - Cite Sanitaire	Saint Nazaire
France	Privé - Hôpital Privé Saint Gregoire	Saint-Grégoire
France	Privé - Clinique de L'Union	Saint-Jean
France	Ch - Centre Hospitalier de Saint-Malo	Saint-Malo
France	Privé - Cmco Côte D'Opale	Saint-Martin-Boulogne
France	Chu - Hôpital Nord - Saint-Étienne	Saint-Priest-en-Jarez
France	Privé - Clinique Trenel	Sainte-Colombe
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 - Hopitaux Du Leman	Thonon-les-Bains
France	Ch - Hôpital Sainte Musse	Toulon
France	Chu - Hôpital Rangueil	Toulouse
France	Chu - Hôpital Trousseau	Tours
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 - Centre Hospitalier Intercommunal	Villeneuve-Saint-Georges

Sponsors (1)

Lead Sponsor	Collaborator
Federation Francophone de Cancerologie Digestive

Country where clinical trial is conducted

France, 

References & Publications (1)

Taïeb J, André 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Overall Survival	Defined as death due to all causes	up to 60 months