Chemotherapy and Immunotherapy as Treatment for MSS Metastatic Colorectal Cancer With High Immune Infiltrate

Colorectal Cancer Metastatic Clinical Trial

— POCHI  

Official title:

Pembrolizumab in Combination With Xelox Bevacizumab in Patients With Microsatellite Stable Mestatic Colorectal Cancer and a High Immune Infiltrate : a Proof of Concept Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04262687
• Other study ID #: FFCD 1703 POCHI
• Status: Recruiting
• Phase: Phase 2
• Start date: April 6, 2021
• Est. completion date: September 30, 2024

Study information

• Verified date: August 2023
• Source: Federation Francophone de Cancerologie Digestive
• Contact: Jeremie BEZ
• Phone: 0380393483
• Email: jeremie.bez[@]u-bourgogne.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 55
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Colorectal Cancer Metastatic
• Colorectal Neoplasms
• High Immune Infiltrate
• Microsatellite Stable

Intervention

Drug:
• Capecitabine
2000 mg/m²/day, from day 1 to 14 of each cycle
• Oxaliplatin
130 mg/m² by IV infusion over 2 hours, on day 1 of each cycle
• Bevacizumab
7.5 mg/kg by IV infusion over 60 minutes, on day 1 of each cycle
• Pembrolizumab
200 mg by IV infusion over 30 minutes, on day 1 of each cycle

Locations

Country	Name	City	State
France	Ch - Centre Hospitalier D'Abbeville	Abbeville
France	Chu - Hôpital Sud	Amiens
France	Privé - Clinique de L'Europe	Amiens
France	Privé - Ico - Site Paul Papin	Angers
France	Privé - Hôpital Privé Pays de Savoie	Annemasse
France	Privé - Hôpital Privé D'Antony	Antony
France	Ch - Hôpital Henri Duffaut	Avignon
France	Prive - Institut Du Cancer Avignon Provence	Avignon
France	Privé - Clinique Capio Balharra	Bayonne
France	Ch - Centre Hospitalier de La Côte Basque	Bayonne CEDEX
France	Ch - Centre Hospitalier de Beauvais	Beauvais
France	Chu - Hôpital Jean Minjoz	Besançon
France	Ch - Centre Hospitalier de Béziers	Béziers
France	Privé - Cac - Clinique Bergonié	Bordeaux
France	Privé - Clinique Tivoli	Bordeaux
France	Privé - Polyclinique Bordeaux Nord	Bordeaux CEDEX
France	Chu - Hôpital Ambroise Paré - Service Anatomie Pathologique	Boulogne
France	Ch - Hôpital Duchenne	Boulogne-sur-Mer
France	Chu - Hôpital Morvan - Institut de Cancérologie	Brest
France	Privé - Clinique Pasteur Lanroze Cfro	Brest
France	Privé - Cac - Centre Francois Baclesse	Caen
France	Privé - Centre Maurice Tubiana	Caen
France	Prive - Polyclinique Du Parc Caen	Caen
France	Privé - Infirmerie Protestante de Lyon	Caluire-et-Cuire
France	Privé - Médipole de Savoie	Challes-les-Eaux
France	Privé - Hôpital Privé Paul D'Egine	Champigny-sur-Marne
France	Ch - Centre Hospitalier de Cholet	Cholet
France	Chu - Hôpital Estaing	Clermont Ferrand
France	Ch - Hôpitaux Civils de Colmar	Colmar
France	Privé - Clinique Saint Come	Compiègne CEDEX
France	Privé - Clinique de Flandre	Coudekerque-Branche
France	Ch - Ghpso - Site de Creil	Creil
France	Ch - Chic de Créteil	Créteil
France	Chu - Hôpital Henri Mondor	Créteil CEDEX
France	Privé - Cac - Centre Georges-Francois Leclerc	Dijon
France	Chu - Hôpital François Mitterrand	Dijon CEDEX
France	Privé - Polyclinique de Blois - 3Eme Etage	La Chaussee St Victor
France	Ch - Chd Vendée	La Roche-sur-Yon
France	CH - GROUPE HOSPITALIER DE La Rochelle RE AUNIS	La Rochelle
France	Privé - Hôpital Franco Britannique	Levallois-Perret
France	Privé - Clinique Du Bois	Lille
France	Chu - Centre Hospitalier Dupuytren	Limoges
France	Ch - Chbs - Hôpital Du Scorff	Lorient CEDEX
France	Privé - Hôpital Jean Mermoz	Lyon
France	Privé - Haliodx	Marseille
France	Privé - Hôpital Saint Joseph	Marseille
France	Privé - Hôpital Europeen	Marseille CEDEX 03
France	Chu - Hôpital La Timone	Marseille CEDEX 5
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	Privé - Polyclinique de Gentilly	Nancy
France	Chu - Hôpital Carémeau	Nîmes
France	Chu - Hôpital Europeen Georges Pompidou	Paris
France	Chu - Hôpital Saint Antoine	Paris
France	Chu - Hôpital Saint-Louis	Paris
France	Privé - Groupe Hospitalier Diaconesses Croix Saint Simon	Paris
France	Privé - Institut Mutualiste Montsouris	Paris
France	Ch - Centre Hospitalier de Pau	Pau CEDEX
France	Privé - Polyclinique Francheville	Perigueux
France	Ch - Centre Hospitalier Saint-Jean	Perpignan
France	Chu - Hôpital Haut Lévêque	Pessac
France	Chu Lyon Sud - Pierre Benite	Pierre-Bénite
France	Privé - Centre Cario Hpca	Plérin
France	Chu - Centre Hospitalier Universitaire de Poitiers - La Miletrie	Poitiers
France	Ch - Chic de Quimper	Quimper
France	Privé - Cac - Institut Jean Godinot	Reims
France	Chu - Centre Hospitalier Universitaire Robert Debre	Reims CEDEX
France	Chu - Centre Hospitalier Universitaire Pontchaillou	Rennes CEDEX 9
France	Ch - Hôpital Drome Nord	Romans-sur-Isère
France	Privé - Clinique Saint-Grégoire	Saint-Grégoire
France	Privé - Cac - Ico - Site René Gauducheau	Saint-Herblain
France	Ch - Centre Hospitalier de Saint-Malo	Saint-Malo
France	Chu - Centre Hospitalier Universitaire de Saint Etienne - Hôpital Nord - Service Hge	Saint-Priest-en-Jarez
France	Privé - Polyclinique Saint-Claude	Saint-Quentin
France	Privé - Clinique Charcot	Sainte-Foy-lès-Lyon
France	Privé - Cac - Paul Strauss / Institut de Cancérologie de Strasbourg Europe	Strasbourg
France	Privé - Clinique Sainte Anne	Strasbourg
France	Chu - Hôpital Foch	Suresnes
France	Privé - Polyclinique de L'Ormeau	Tarbes
France	Ch - Hôpital Sainte Musse	Toulon
France	Chu - Hôpital Trousseau	Tours CEDEX 9
France	Ch - Centre Hospitalier de Valenciennes	Valenciennes
France	Chu - Hôpital Bradois	Vandœuvre-lès-Nancy
France	Privé - Cac - Institut de Cancerologie de Lorraine	Vandœuvre-lès-Nancy
France	Chu - Hôpital Paul Brousse	Villejuif
France	Privé - Cac - Institut Gustave Roussy	Villejuif

Sponsors (1)

Lead Sponsor	Collaborator
Federation Francophone de Cancerologie Digestive

Country where clinical trial is conducted

France, 

References & Publications (21)

Carbonnel F, Soularue E, Coutzac C, Chaput N, Mateus C, Lepage P, Robert C. Inflammatory bowel disease and cancer response due to anti-CTLA-4: is it in the flora? Semin Immunopathol. 2017 Apr;39(3):327-331. doi: 10.1007/s00281-016-0613-x. Epub 2017 Jan 16. — View Citation

Caulet M, Lecomte T, Bouche O, Rollin J, Gouilleux-Gruart V, Azzopardi N, Leger J, Borg C, Douillard JY, Manfredi S, Smith D, Capitain O, Ferru A, Moussata D, Terrebone E, Paintaud G, Ternant D. Bevacizumab Pharmacokinetics Influence Overall and Progression-Free Survival in Metastatic Colorectal Cancer Patients. Clin Pharmacokinet. 2016 Nov;55(11):1381-1394. doi: 10.1007/s40262-016-0406-3. — View Citation

Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, Allen B, Bozic I, Reiter JG, Nowak MA, Kinzler KW, Oliner KS, Vogelstein B. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012 Jun 28;486(7404):537-40. doi: 10.1038/nature11219. — View Citation

Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012 Mar 15;12(4):298-306. doi: 10.1038/nrc3245. — View Citation

Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236. Epub 2017 Nov 2. — View Citation

Gordon MS, Margolin K, Talpaz M, Sledge GW Jr, Holmgren E, Benjamin R, Stalter S, Shak S, Adelman D. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol. 2001 Feb 1;19(3):843-50. doi: 10.1200/JCO.2001.19.3.843. — View Citation

Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, McDermott DF, Powderly JD, Gettinger SN, Kohrt HE, Horn L, Lawrence DP, Rost S, Leabman M, Xiao Y, Mokatrin A, Koeppen H, Hegde PS, Mellman I, Chen DS, Hodi FS. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014 Nov 27;515(7528):563-7. doi: 10.1038/nature14011. — View Citation

Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, Adamow M, Kuk D, Panageas KS, Carrera C, Wong P, Quagliarello F, Wubbenhorst B, D'Andrea K, Pauken KE, Herati RS, Staupe RP, Schenkel JM, McGettigan S, Kothari S, George SM, Vonderheide RH, Amaravadi RK, Karakousis GC, Schuchter LM, Xu X, Nathanson KL, Wolchok JD, Gangadhar TC, Wherry EJ. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017 May 4;545(7652):60-65. doi: 10.1038/nature22079. Epub 2017 Apr 10. — View Citation

Kamphorst AO, Wieland A, Nasti T, Yang S, Zhang R, Barber DL, Konieczny BT, Daugherty CZ, Koenig L, Yu K, Sica GL, Sharpe AH, Freeman GJ, Blazar BR, Turka LA, Owonikoko TK, Pillai RN, Ramalingam SS, Araki K, Ahmed R. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science. 2017 Mar 31;355(6332):1423-1427. doi: 10.1126/science.aaf0683. Epub 2017 Mar 9. — View Citation

Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, Bridonneau C, Jegou S, Hoffmann TW, Natividad JM, Brot L, Taleb S, Couturier-Maillard A, Nion-Larmurier I, Merabtene F, Seksik P, Bourrier A, Cosnes J, Ryffel B, Beaugerie L, Launay JM, Langella P, Xavier RJ, Sokol H. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016 Jun;22(6):598-605. doi: 10.1038/nm.4102. Epub 2016 May 9. — View Citation

Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, Bencardino K, Cercek A, Chen CT, Veronese S, Zanon C, Sartore-Bianchi A, Gambacorta M, Gallicchio M, Vakiani E, Boscaro V, Medico E, Weiser M, Siena S, Di Nicolantonio F, Solit D, Bardelli A. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012 Jun 28;486(7404):532-6. doi: 10.1038/nature11156. — View Citation

Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015 Apr;36(4):265-76. doi: 10.1016/j.it.2015.02.008. Epub 2015 Mar 18. — View Citation

Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Zheng H, Xie Y, Tap J, Lepage P, Bertalan M, Batto JM, Hansen T, Le Paslier D, Linneberg A, Nielsen HB, Pelletier E, Renault P, Sicheritz-Ponten T, Turner K, Zhu H, Yu C, Li S, Jian M, Zhou Y, Li Y, Zhang X, Li S, Qin N, Yang H, Wang J, Brunak S, Dore J, Guarner F, Kristiansen K, Pedersen O, Parkhill J, Weissenbach J; MetaHIT Consortium; Bork P, Ehrlich SD, Wang J. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010 Mar 4;464(7285):59-65. doi: 10.1038/nature08821. — View Citation

Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragon L, Jacquelot N, Qu B, Ferrere G, Clemenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018 Jan 5;359(6371):91-97. doi: 10.1126/science.aan3706. Epub 2017 Nov 2. — View Citation

Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011 Jun;11(6):426-37. doi: 10.1038/nrc3066. Epub 2011 May 12. — View Citation

Sokol H, Leducq V, Aschard H, Pham HP, Jegou S, Landman C, Cohen D, Liguori G, Bourrier A, Nion-Larmurier I, Cosnes J, Seksik P, Langella P, Skurnik D, Richard ML, Beaugerie L. Fungal microbiota dysbiosis in IBD. Gut. 2017 Jun;66(6):1039-1048. doi: 10.1136/gutjnl-2015-310746. Epub 2016 Feb 3. — View Citation

Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P. About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta. 2001 Nov;313(1-2):139-42. doi: 10.1016/s0009-8981(01)00665-9. — View Citation

Thierry AR, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet F, Gillet B, Gongora C, Dechelotte P, Robert B, Del Rio M, Lamy PJ, Bibeau F, Nouaille M, Loriot V, Jarrousse AS, Molina F, Mathonnet M, Pezet D, Ychou M. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat Med. 2014 Apr;20(4):430-5. doi: 10.1038/nm.3511. Epub 2014 Mar 23. — View Citation

Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014 Nov 27;515(7528):568-71. doi: 10.1038/nature13954. — View Citation

Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Berard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, Elson CO, Dore J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013 Nov 22;342(6161):971-6. doi: 10.1126/science.1240537. — View Citation

Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013 Mar 29;339(6127):1546-58. doi: 10.1126/science.1235122. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The rate of patients alive and without progression at 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	10 months after inclusion
Secondary	Overall survival	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	Up to 2 years after the end of the treatment
Secondary	Histological response in case of secondary resection	Response evaluated according to the TRG (Rubbia-Brandt L et al. Annals Oncol 2007), for patients who underwent a secondary resection	Up to 2 years after the end of the treatment