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Fluorouracil

Avelumab

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Immunoglobulin G

Immunoglobulins, Intravenous

Antineoplastic Agents, Immunological

Cola

After standard adjuvant 5FU based chemotherapy, patients will have no active intervention but will start standard follow up.

Avelumab is a fully human monoclonal antibody (MoAb) of the immunoglobulin G (IgG) 1 subtype which specifically binds to the PD-L1 cell surface ligand and blocks its interaction with the PD-1 cell surface receptor.

Tony Dhillon, Bsc,FRCP, PhD

The purpose of this study is to determine if dMMR and/or POLE exonuclease domain mutant stage III colon cancer patients gain clinical benefit (i.e. improvement in disease free and overall survival) from PD-L1 inhibitors after standard fluoropyrimidine-based adjuvant chemotherapy.

Avelumab binds PD-L1 and blocks the interaction between PD-L1 and PD-1. This removes the suppressive effects of PD-L1 on anti-tumour CD8+ T cells, resulting in the restoration of cytotoxic T cell response.

The rationale of giving Avelumab after standard adjuvant chemotherapy to this well-defined, molecularly-selected, group is based on the fact that dMMR and POLE exonuclease domain mutant CRCs have a highly and ultra-mutated genetic profile, respectively, thus leading to a high number of neo-antigens with associated over expression of immune checkpoint related proteins. This profile is expected to be highly responsive to checkpoint inhibition as suggested by data of PD-1 inhibitors in dMMR/MSI-H metastatic CRCs.

If this study meets the primary endpoint, using Avelumab in the adjuvant setting following standard chemotherapy would become the standard of care for patients with dMMR and/or POLE exonuclease domain mutant colon cancers. Furthermore, given the availability of molecular markers for patient selection, funders of healthcare would be more likely to fund this treatment.

This study also provides a unique opportunity to conduct translational research analyses on pre- and post-treatment tumour tissue samples and blood samples from dMMR or POLE mutant CRC patients treated with the checkpoint inhibitor Avelumab.

This is an open-label, multi-centre, randomised, phase III trial comparing standard fluoropyrimidine based adjuvant chemotherapy followed by Avelumab (experimental arm) with standard fluoropyrimidine-based adjuvant chemotherapy alone (control arm) in patients who have undergone radical surgical resection for stage III dMMR or POLE exonuclease domain mutant colon cancer. Patients will be stratified in a 1:1 ratio for dMMR status, POLE mutation and type of adjuvant chemotherapy (i.e., 24 weeks of single agent capecitabine chemotherapy versus 12 weeks of CAPOX chemotherapy).

According to the statistical design, 402 patients (201 per arm) are to be randomised. It is expected that approximately 4000 participants will need to be screened in order to recruit 402 patients to the study, assuming an incidence of dMMR of 10-15% and an incidence of POLE mutations of 7% in under 50s (unpublished data from Tomlinson group). Considering the time required to obtain local approval and to initiate all participating centres, the study is expected to take up to 36 months to complete accrual.

There are no proscriptive criteria for surgical resection of the primary tumour in this trial. It is however expected that resection of the tumour will be undertaken in the elective setting by a colorectal specialist surgeon.

Tumour MMR status will be routinely tested locally as per NICE guidelines (either in the pre-operative biopsy or resection specimen). Subjects whose tumours are dMMR can sign the main study consent and undergo the study screening procedures. If they are found to fulfil all eligibility criteria, then they will be randomised. Subjects who are below 50 and whose tumours are pMMR, will be asked to sign a prescreening consent for the centralised analysis of POLE exonuclease domain mutations. This will be done at Oxford Molecular Diagnostics Centre, John Radcliffe Hospital, Headington, Oxford. Those who have tumours harbouring these mutations can sign the main study consent and undergo the study screening procedures. If they are found to fulfil all eligibility criteria, then they will be randomised.

All eligible patients who are randomised will receive standard fluoropyrimidine-based adjuvant chemotherapy for 12 or 24 weeks depending on the decision of the local investigator. The choice of adjuvant chemotherapy (i.e., 24 weeks of single agent fluoropyrimidine chemotherapy or 12 weeks of doublet, oxaliplatin-based chemotherapy) must be declared by the investigator at study entry before randomisation. Type of adjuvant chemotherapy (i.e., 24 weeks of single agent capecitabine or 12 weeks of capecitabine plus oxaliplatin). will be used as stratification factor alongside MMR status and POLE mutation.

At the end of adjuvant chemotherapy, patients who are randomised to the investigational arm, will receive additional 24 weeks of treatment with Avelumab.

After completion of treatment, all subjects will be followed up for up to 7 years from the start of adjuvant chemotherapy.

Correlative biomarker analyses will be conducted as part of the translational study in tumour tissue samples from the resection specimens, tumour tissue samples from the relapsed tumour (if applicable, feasible and upon patient consent) and serial blood samples collected at study entry, during adjuvant treatment and follow-up.

\*\*\* POLEM encountered significant recruitment challenges. Recruitment into the study was halted at 30 patients enrolled from the original target of 402.

Avelumab Plus 5-FU Based Chemotherapy as Adjuvant Treatment for Stage 3 MSI-High or POLE Mutant Colon Cancer

POLEM:Avelumab Plus 5-FU Based Chemotherapy as Adjuvant Treatment for Stage 3 MSI-High or POLE Exonuclease Domain Mutant Colon Cancer: A Phase 3 Randomised Study

Disease-free survival (DFS) at 3 years. DFS is measured from the date of randomisation to the date of first relapse (radiological or clinical) or death from any cause.

Overall survival (OS) at 5 and 7 years. OS is measured from the date of randomisation to date of death from any cause.

Health-related quality of life (HRQoL) quantified by collection of quality of life data using the EORTC QLQ C-30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire)

Toxicity according to the NCI-CTCAE (Common Terminology Criteria for Adverse Events) version 4.0.It uses a range of grades from 1 to 5. Specific conditions and symptoms have values for each level, guideline is: 1 - Mild 2 - Moderate 3 - Severe 4 - Life-threatening 5 - Death

University of Surrey

University of Oxford

Merck KGaA, Darmstadt, Germany

Royal Marsden NHS Foundation Trust

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Avelumab Plus 5-FU Based Chemotherapy as Adjuvant Treatment for Stage 3 MSI-High or POLE Mutant Colon Cancer	NCT03827044	POLE Exonucleas... Microsatellite ... Stage III Colon...	Avelumab	18 Years -	Royal Marsden NHS Foundation Trust
Avelumab Plus 5-FU Based Chemotherapy as Adjuvant Treatment for Stage 3 MSI-High or POLE Mutant Colon Cancer	NCT03827044	POLE Exonucleas... Microsatellite ... Stage III Colon...	Avelumab	18 Years -	Royal Marsden NHS Foundation Trust

Spots Global Cancer Trial Database for pole exonuclease domain mutant