Chemotherapy and Immunotherapy as Treatment for MSS Metastatic Colorectal Cancer With High Immune Infiltrate
POCHI
Pembrolizumab in Combination With Xelox Bevacizumab in Patients With Microsatellite Stable Mestatic Colorectal Cancer and a High Immune Infiltrate : a Proof of Concept Study
1 other identifier
interventional
55
1 country
88
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_2
Started Apr 2021
Typical duration for phase_2
88 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
February 6, 2020
CompletedFirst Posted
Study publicly available on registry
February 10, 2020
CompletedStudy Start
First participant enrolled
April 6, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 30, 2024
CompletedStudy Completion
Last participant's last visit for all outcomes
September 30, 2024
CompletedAugust 18, 2023
August 1, 2023
3.5 years
February 6, 2020
August 16, 2023
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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 Outcomes (2)
Overall survival
Up to 2 years after the end of the treatment
Histological response in case of secondary resection
Up to 2 years after the end of the treatment
Study Arms (1)
Immunotherapy + chemotherapy
EXPERIMENTALXelox bevacizumab plus pembrolizumab every 3 weeks up until disease progression, unacceptable toxicity, refusal by the patient, withdrawal of consent, pregnancy or decision by the investigator.
Interventions
130 mg/m² by IV infusion over 2 hours, on day 1 of each cycle
7.5 mg/kg by IV infusion over 60 minutes, on day 1 of each cycle
200 mg by IV infusion over 30 minutes, on day 1 of each cycle
Eligibility Criteria
You may qualify if:
- 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
You may not qualify if:
- 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
- +7 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (88)
Ch - Centre Hospitalier D'Abbeville
Abbeville, 80090, France
Chu - Hôpital Sud
Amiens, France
Privé - Clinique de L'Europe
Amiens, France
Privé - Ico - Site Paul Papin
Angers, 49055, France
Privé - Hôpital Privé Pays de Savoie
Annemasse, 74100, France
Privé - Hôpital Privé D'Antony
Antony, 92160, France
Ch - Hôpital Henri Duffaut
Avignon, 84902, France
Prive - Institut Du Cancer Avignon Provence
Avignon, France
Ch - Centre Hospitalier de La Côte Basque
Bayonne, 64100, France
Privé - Clinique Capio Balharra
Bayonne, France
Ch - Centre Hospitalier de Beauvais
Beauvais, 60021, France
Chu - Hôpital Jean Minjoz
Besançon, 25030, France
Ch - Centre Hospitalier de Béziers
Béziers, France
Privé - Cac - Clinique Bergonié
Bordeaux, 33076, France
Privé - Polyclinique Bordeaux Nord
Bordeaux, 33077, France
Privé - Clinique Tivoli
Bordeaux, France
Chu - Hôpital Ambroise Paré - Service Anatomie Pathologique
Boulogne, France
Ch - Hôpital Duchenne
Boulogne-sur-Mer, France
Chu - Hôpital Morvan - Institut de Cancérologie
Brest, 29609, France
Privé - Clinique Pasteur Lanroze Cfro
Brest, France
Privé - Centre Maurice Tubiana
Caen, 14000, France
Privé - Cac - Centre Francois Baclesse
Caen, 14076, France
Prive - Polyclinique Du Parc Caen
Caen, France
Privé - Infirmerie Protestante de Lyon
Caluire-et-Cuire, 69300, France
Privé - Médipole de Savoie
Challes-les-Eaux, 73190, France
Privé - Hôpital Privé Paul D'Egine
Champigny-sur-Marne, 94500, France
Ch - Centre Hospitalier de Cholet
Cholet, 49300, France
Chu - Hôpital Estaing
Clermont-Ferrand, France
Ch - Hôpitaux Civils de Colmar
Colmar, 68024, France
Privé - Clinique Saint Come
Compiègne, 60204, France
Privé - Clinique de Flandre
Coudekerque-Branche, 59210, France
Ch - Ghpso - Site de Creil
Creil, 60100, France
Chu - Hôpital Henri Mondor
Créteil, 94000, France
Ch - Chic de Créteil
Créteil, France
Chu - Hôpital François Mitterrand
Dijon, 21079, France
Privé - Cac - Centre Georges-Francois Leclerc
Dijon, 21079, France
Privé - Polyclinique de Blois - 3Eme Etage
La Chaussée-Saint-Victor, 41260, France
Ch - Chd Vendée
La Roche-sur-Yon, 85925, 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, 87042, France
Ch - Chbs - Hôpital Du Scorff
Lorient, 56322, France
Privé - Hôpital Jean Mermoz
Lyon, 69008, France
Privé - Hôpital Saint Joseph
Marseille, 13008, France
Privé - Hôpital Europeen
Marseille, 13331, France
Chu - Hôpital La Timone
Marseille, 13385, France
Privé - Haliodx
Marseille, France
Ch - Ghi - Groupe Hospitalier de L'Est Francilien - Site de Meaux
Meaux, 77100, France
Ch - Hôpital Layné
Mont-de-Marsan, 40 000, France
Privé - Centre Azureen de Cancerologie
Mougins, 06250, France
Privé - Hôpital Prive Arnault Tzanck
Mougins, 06250, France
Privé - Polyclinique de Gentilly
Nancy, 54100, France
Chu - Hôpital Carémeau
Nîmes, 30029, France
Privé - Institut Mutualiste Montsouris
Paris, 75014, France
Chu - Hôpital Europeen Georges Pompidou
Paris, 75015, France
Privé - Groupe Hospitalier Diaconesses Croix Saint Simon
Paris, 75020, France
Chu - Hôpital Saint Antoine
Paris, France
Chu - Hôpital Saint-Louis
Paris, France
Ch - Centre Hospitalier de Pau
Pau, 64046, France
Ch - Centre Hospitalier Saint-Jean
Perpignan, France
Chu - Hôpital Haut Lévêque
Pessac, France
Privé - Polyclinique Francheville
Périgueux, 24004, France
Chu Lyon Sud - Pierre Benite
Pierre-Bénite, 69495, France
Privé - Centre Cario Hpca
Plérin, France
Chu - Centre Hospitalier Universitaire de Poitiers - La Miletrie
Poitiers, 86021, France
Ch - Chic de Quimper
Quimper, France
Chu - Centre Hospitalier Universitaire Robert Debre
Reims, 51092, France
Privé - Cac - Institut Jean Godinot
Reims, 51726, France
Chu - Centre Hospitalier Universitaire Pontchaillou
Rennes, 35033, France
Ch - Hôpital Drome Nord
Romans-sur-Isère, 26100, France
Privé - Clinique Saint-Grégoire
Saint-Grégoire, France
Privé - Cac - Ico - Site René Gauducheau
Saint-Herblain, 44805, France
Chu - Centre Hospitalier Universitaire de Saint Etienne - Hôpital Nord - Service Hge
Saint-Priest-en-Jarez, 42270, France
Privé - Polyclinique Saint-Claude
Saint-Quentin, 02100, France
Privé - Clinique Charcot
Sainte-Foy-lès-Lyon, 69510, France
Ch - Centre Hospitalier de Saint-Malo
St-Malo, 35403, France
Privé - Clinique Sainte Anne
Strasbourg, 67000, France
Privé - Cac - Paul Strauss / Institut de Cancérologie de Strasbourg Europe
Strasbourg, 67065, France
Chu - Hôpital Foch
Suresnes, 92151, France
Privé - Polyclinique de L'Ormeau
Tarbes, 65000, France
Ch - Hôpital Sainte Musse
Toulon, 83000, France
Chu - Hôpital Trousseau
Tours, 37044, France
Ch - Centre Hospitalier de Valenciennes
Valenciennes, 59300, France
Privé - Cac - Institut de Cancerologie de Lorraine
Vandœuvre-lès-Nancy, 54519, France
Chu - Hôpital Bradois
Vandœuvre-lès-Nancy, France
Chu - Hôpital Paul Brousse
Villejuif, 94804, France
Privé - Cac - Institut Gustave Roussy
Villejuif, France
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MeSH Terms
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
David TOUGERON, MD,PHD
CHU Poitiers
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
February 6, 2020
First Posted
February 10, 2020
Study Start
April 6, 2021
Primary Completion
September 30, 2024
Study Completion
September 30, 2024
Last Updated
August 18, 2023
Record last verified: 2023-08
Data Sharing
- IPD Sharing
- Will not share