Informations générales (source: ClinicalTrials.gov)
Pembrolizumab in Combination With Xelox Bevacizumab in Patients With Microsatellite Stable Mestatic Colorectal Cancer and a High Immune Infiltrate : a Proof of Concept Study (POCHI)
Interventional
Phase 2
Federation Francophone de Cancerologie Digestive (Voir sur ClinicalTrials)
avril 2021
septembre 2024
29 juin 2024
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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| HOPITAL FOCH | MAY MABRO | 30/12/2024 08:02:23 | Contacter | ||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| AP-HP - Hôpital Henri Mondor-Albert Chenevier | Isabelle BAUMGAERTNER, Dr | Contact (sur clinicalTrials) | |||
| CLCC INSTITUT GUSTAVE ROUSSY | Contact (sur clinicalTrials) | ||||
| EFS IDF SITE HOP EUROPEEN G POMPIDOU | Julien TAIEB, Dr | Contact (sur clinicalTrials) | |||
| GRPE HOSP DIACONESSES-CROIX ST-SIMON | Olivier DUBREUIL, Dr | Contact (sur clinicalTrials) | |||
| IFSI HÔPITAL PAUL BROUSSE | Ayhan ULUSAKARYA, Dr | Contact (sur clinicalTrials) | |||
| Les établissements hors Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Ch - Centre Hospitalier de Béziers - Béziers - France | Mohamed RAMDANI, Dr | Contact (sur clinicalTrials) | |||
| Ch - Centre Hospitalier Saint-Jean - Perpignan - France | Faiza KHEMISSA, Dr | Contact (sur clinicalTrials) | |||
| Ch - Hôpital Duchenne - Boulogne-sur-Mer - France | Vincent BOURGEOIS, Dr | Contact (sur clinicalTrials) | |||
| Ch - Hôpital Layné - 40 000 - Mont-de-Marsan - France | Patrick TEXEREAU, Dr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Estaing - Clermont Ferrand - France | Caroline PETORIN, Dr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Saint Antoine - Paris - France | Contact (sur clinicalTrials) | ||||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Ch - Centre Hospitalier D'Abbeville - 80090 - Abbeville - France | Mathieu Pauwels, Dr | Contact (sur clinicalTrials) | |||
| Ch - Centre Hospitalier de Beauvais - 60021 - Beauvais - France | Fayçal HOCINE, Dr | Contact (sur clinicalTrials) | |||
| Ch - Centre Hospitalier de Cholet - 49300 - Cholet - France | You-Heng LAM, Dr | Contact (sur clinicalTrials) | |||
| Ch - Centre Hospitalier de La Côte Basque - 64100 - Bayonne CEDEX - France | Franck AUDEMAR, Dr | Contact (sur clinicalTrials) | |||
| Ch - Centre Hospitalier de Pau - 64046 - Pau CEDEX - France | Juliette THAURY, Dr | Contact (sur clinicalTrials) | |||
| Ch - Centre Hospitalier de Saint-Malo - 35403 - Saint-Malo - France | Anaïs BODERE, Dr | Contact (sur clinicalTrials) | |||
| Ch - Centre Hospitalier de Valenciennes - 59300 - Valenciennes - France | Eduardo BARRASCOUT, Dr | Contact (sur clinicalTrials) | |||
| Ch - Chbs - Hôpital Du Scorff - 56322 - Lorient CEDEX - France | Joëlle EGRETEAU, Dr | Contact (sur clinicalTrials) | |||
| Ch - Chd Vendée - 85925 - La Roche-sur-Yon - France | Margot LALY, Dr | Contact (sur clinicalTrials) | |||
| Ch - Chic de Créteil - Créteil - France | Isabelle COJEAN-ZELEK, Dr | Contact (sur clinicalTrials) | |||
| Ch - Chic de Quimper - Quimper - France | Karine BIDEAU, Dr | Contact (sur clinicalTrials) | |||
| Ch - Ghi - Groupe Hospitalier de L'Est Francilien - Site de Meaux - 77100 - Meaux - France | Christophe LOCHER, Dr | Contact (sur clinicalTrials) | |||
| Ch - Ghpso - Site de Creil - 60100 - Creil - France | Elisabeth CAROLA, Dr | Contact (sur clinicalTrials) | |||
| CH - GROUPE HOSPITALIER DE La Rochelle RE AUNIS - La Rochelle - France | Contact (sur clinicalTrials) | ||||
| Ch - Hôpital Drome Nord - 26100 - Romans-sur-Isère - France | Marie-Claude GOUTTEBEL, Dr | Contact (sur clinicalTrials) | |||
| Ch - Hôpital Henri Duffaut - 84902 - Avignon - France | Thibault BROTELLE, Dr | Contact (sur clinicalTrials) | |||
| Ch - Hôpital Sainte Musse - 83000 - Toulon - France | Camille SIBERTIN-BLANC, Dr | Contact (sur clinicalTrials) | |||
| Ch - Hôpitaux Civils de Colmar - 68024 - Colmar - France | Amalia TOPOLSCKI, Dr | Contact (sur clinicalTrials) | |||
| Chu - Centre Hospitalier Dupuytren - 87042 - Limoges - France | Valerie LE BRUN LY, Dr | Contact (sur clinicalTrials) | |||
| Chu - Centre Hospitalier Universitaire de Poitiers - La Miletrie - 86021 - Poitiers - France | David TOUGERON, Pr | Contact (sur clinicalTrials) | |||
| Chu - Centre Hospitalier Universitaire de Saint Etienne - Hôpital Nord - Service Hge - 42270 - Saint-Priest-en-Jarez - France | Jean-Marc PHELIP, Pr | Contact (sur clinicalTrials) | |||
| Chu - Centre Hospitalier Universitaire Pontchaillou - 35033 - Rennes CEDEX 9 - France | Astrid LIEVRE, Pr | Contact (sur clinicalTrials) | |||
| Chu - Centre Hospitalier Universitaire Robert Debre - 51092 - Reims CEDEX - France | Olivier BOUCHE, Pr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Ambroise Paré - Service Anatomie Pathologique - Boulogne - France | Jean-François EMILE | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Bradois - Vandœuvre-lès-Nancy - France | Anthony LOPEZ, Dr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Carémeau - 30029 - Nîmes - France | Valérie PHOUTTHASANG, Dr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital François Mitterrand - 21079 - Dijon CEDEX - France | Sylvain MANFREDI, Pr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Haut Lévêque - Pessac - France | Denis SMITH | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Jean Minjoz - 25030 - Besançon - France | Stéfano KIM, Dr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital La Timone - 13385 - Marseille CEDEX 5 - France | Laétitia DAHAN, Pr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Morvan - Institut de Cancérologie - 29609 - Brest - France | Jean-Philippe METGES, Dr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Saint-Louis - Paris - France | Thomas APARICIO, Pr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Sud - Amiens - France | Vincent HAUTEFEUILLE, Dr | Contact (sur clinicalTrials) | |||
| Chu - Hôpital Trousseau - 37044 - Tours CEDEX 9 - France | Thierry LECOMTE, Pr | Contact (sur clinicalTrials) | |||
| Chu Lyon Sud - Pierre Benite - 69495 - Pierre-Bénite - France | Marion CHAUVENET, Dr | Contact (sur clinicalTrials) | |||
| Privé - Cac - Centre Francois Baclesse - 14076 - Caen - France | Stéphane CORBINAIS, Dr | Contact (sur clinicalTrials) | |||
| Privé - Cac - Centre Georges-Francois Leclerc - 21079 - Dijon - France | François GHIRINGHELLI, Pr | Contact (sur clinicalTrials) | |||
| Privé - Cac - Clinique Bergonié - 33076 - Bordeaux - France | Simon PERNOT, Dr | Contact (sur clinicalTrials) | |||
| Privé - Cac - Ico - Site René Gauducheau - 44805 - Saint-Herblain - France | Judith RAIMBOURG, Dr | Contact (sur clinicalTrials) | |||
| Privé - Cac - Institut de Cancerologie de Lorraine - 54519 - Vandœuvre-lès-Nancy - France | Pierre LEHAIR, Dr | Contact (sur clinicalTrials) | |||
| Privé - Cac - Institut Jean Godinot - 51726 - Reims - France | Damien BOTSEN, Dr | Contact (sur clinicalTrials) | |||
| Privé - Cac - Paul Strauss / Institut de Cancérologie de Strasbourg Europe - 67065 - Strasbourg - France | Meher BEN ABDELGHANI, Dr | Contact (sur clinicalTrials) | |||
| Privé - Centre Azureen de Cancerologie - 06250 - Mougins - France | Benjamin HOCH, Dr | Contact (sur clinicalTrials) | |||
| Privé - Centre Cario Hpca - Plérin - France | Contact (sur clinicalTrials) | ||||
| Privé - Centre Maurice Tubiana - 14000 - Caen - France | Emmanuel SEVIN, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique Capio Balharra - Bayonne - France | Marjorie FAURE, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique Charcot - 69510 - Sainte-Foy-lès-Lyon - France | Clémence THEVENET, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique de Flandre - 59210 - Coudekerque-Branche - France | Laurence BOUTAUD DE LA COMBE CHOSSIERE, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique de L'Europe - Amiens - France | Michel GOZY, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique Du Bois - Lille - France | Eric Yaovi Mesan AMELA, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique Pasteur Lanroze Cfro - Brest - France | Véronique JESTIN LE TALLEC, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique Saint Come - 60204 - Compiègne CEDEX - France | Kaïs ALDABBAGH, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique Sainte Anne - 67000 - Strasbourg - France | Louis-Marie DOURTHE, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique Saint-Grégoire - Saint-Grégoire - France | Clément PERRET, Dr | Contact (sur clinicalTrials) | |||
| Privé - Clinique Tivoli - Bordeaux - France | Valérie COCHIN, Dr | Contact (sur clinicalTrials) | |||
| Privé - Haliodx - Marseille - France | Isabelle BOQUET | Contact (sur clinicalTrials) | |||
| Privé - Hôpital Europeen - 13331 - Marseille CEDEX 03 - France | Yves RINALDI, Dr | Contact (sur clinicalTrials) | |||
| Privé - Hôpital Franco Britannique - Levallois-Perret - France | Benoist CHIBAUDEL, Dr | Contact (sur clinicalTrials) | |||
| Privé - Hôpital Jean Mermoz - 69008 - Lyon - France | Chloé VERNET, Dr | Contact (sur clinicalTrials) | |||
| Privé - Hôpital Prive Arnault Tzanck - 06250 - Mougins - France | Benjamin HOCH, Dr | Contact (sur clinicalTrials) | |||
| Privé - Hôpital Privé D'Antony - 92160 - Antony - France | Anne THIROT BIDAULT, Dr | Contact (sur clinicalTrials) | |||
| Privé - Hôpital Privé Paul D'Egine - 94500 - Champigny-sur-Marne - France | Adil CHAFAI EL ALAOUI, Dr | Contact (sur clinicalTrials) | |||
| Privé - Hôpital Privé Pays de Savoie - 74100 - Annemasse - France | Wulfran CACHEUX, Dr | Contact (sur clinicalTrials) | |||
| Privé - Hôpital Saint Joseph - 13008 - Marseille - France | Hervé PERRIER, Dr | Contact (sur clinicalTrials) | |||
| Privé - Ico - Site Paul Papin - 49055 - Angers - France | Judith RAIMBOURG, Dr | Contact (sur clinicalTrials) | |||
| Privé - Infirmerie Protestante de Lyon - 69300 - Caluire-et-Cuire - France | Johannes HARTWIG, Dr | Contact (sur clinicalTrials) | |||
| Prive - Institut Du Cancer Avignon Provence - Avignon - France | Rania BOUSTANY-GRENIER | Contact (sur clinicalTrials) | |||
| Privé - Institut Mutualiste Montsouris - 75014 - Paris - France | Christophe LOUVET, Dr | Contact (sur clinicalTrials) | |||
| Privé - Médipole de Savoie - 73190 - Challes-les-Eaux - France | Christine REBISCHUNG, Dr | Contact (sur clinicalTrials) | |||
| Privé - Polyclinique Bordeaux Nord - 33077 - Bordeaux CEDEX - France | Cédric LECAILLE, Dr | Contact (sur clinicalTrials) | |||
| Privé - Polyclinique de Blois - 3Eme Etage - 41260 - La Chaussee St Victor - France | Philippe LAPLAIGE, Dr | Contact (sur clinicalTrials) | |||
| Privé - Polyclinique de Gentilly - 54100 - Nancy - France | Fabien BROCARD, Dr | Contact (sur clinicalTrials) | |||
| Privé - Polyclinique de L'Ormeau - 65000 - Tarbes - France | Philippe AYELA, Dr | Contact (sur clinicalTrials) | |||
| Prive - Polyclinique Du Parc Caen - Caen - France | Emmanuel SEVIN | Contact (sur clinicalTrials) | |||
| Privé - Polyclinique Francheville - 24004 - Perigueux - France | Laurent CANY, Dr | Contact (sur clinicalTrials) | |||
| Privé - Polyclinique Saint-Claude - 02100 - Saint-Quentin - France | Pierre VANELSLANDER, Dr | Contact (sur clinicalTrials) | |||
Critères
Tous
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
- 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
- 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