Chemotherapy and Immunotherapy as Treatment for MSS Metastatic Colorectal Cancer With High Immune Infiltrate (POCHI)
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|ClinicalTrials.gov Identifier: NCT04262687|
Recruitment Status : Not yet recruiting
First Posted : February 10, 2020
Last Update Posted : July 30, 2020
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.
|Condition or disease||Intervention/treatment||Phase|
|Colorectal Cancer Metastatic High Immune Infiltrate Microsatellite Stable||Drug: Capecitabine Drug: Oxaliplatin Drug: Bevacizumab Drug: Pembrolizumab||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||55 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Estimated Study Start Date :||September 30, 2020|
|Estimated Primary Completion Date :||December 31, 2022|
|Estimated Study Completion Date :||December 31, 2023|
Experimental: Immunotherapy + chemotherapy
Xelox 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.
2000 mg/m²/day, from day 1 to 14 of each cycle
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
- Evaluate the efficacy of pembrolizumab in combination with XELOX and bevacizumab as 1st line treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC) with a high immune infiltrate [ Time Frame: From date of inclusion until 10 months after inclusion ]the percentage of patients alive and without progression at 10 months
- Overall survival [ Time Frame: through study completion, an average of 2 year ]date of death of patient (whatever the cause) or date of last news if patient is alive.
- Adverse events evaluated according to NCI-CTC v4.0 [ Time Frame: total duration of treatment and 30 days after treatment ]Evaluated according to NCI-CTC v4.0 criteria and described by maximum grade
- Histological response in case of secondary resection [ Time Frame: through study completion, an average of 2 year ]evaluated according to the TRG (Rubbia-Brandt L et al. Annals Oncol 2007), in patients who underwent a secondary resection
- Outcome of tumour markers [ Time Frame: through study completion, an average of 2 year ]CEA and CA19.9: the evolution of the markers will be analyzed by a graphic representation of the percentage change from baseline rate.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04262687
|Contact: Jeremie BEZemail@example.com|
|Principal Investigator:||David TOUGERON, MD,PHD||CHU POITIERS|