NCT03827044: POLEM

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

Terminated Phase 3 Last updated 7 October 2022

What this trial tests

Phase 3 trial testing Avelumab in POLE Exonuclease Mutant Colon Cancer in 30 participants. Terminated before completion.

Timeline

31 August 2018

Primary endpoint
5 January 2021

5 January 2022

Quick facts

Lead sponsor	Royal Marsden NHS Foundation Trust
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	30
Start date	31 August 2018
Primary completion	5 January 2021
Estimated completion	5 January 2022
Sites	1 location across United Kingdom

Drugs / interventions tested

• Avelumab (avelumab) — full drug profile →

Conditions studied

• POLE Exonuclease Mutant Colon Cancer — all drugs for POLE Exonuclease Mutant Colon Cancer →
• Microsatellite Instability — all drugs for Microsatellite Instability →
• Stage III Colon Cancer — all drugs for Stage III Colon Cancer →

Sponsor

Royal Marsden NHS Foundation Trust

Who can join

18 and older, any sex, with POLE Exonuclease Mutant Colon Cancer or Microsatellite Instability. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Comprehensive review of targeted therapy for colorectal cancer.
   Xie YH, Chen YX, Fang JY. · · 2020 · cited 1162× · PMID 32296018 · DOI 10.1038/s41392-020-0116-z
2. Neoantigens: promising targets for cancer therapy.
   Xie N, Shen G, Gao W, Huang Z, et al · · 2023 · cited 713× · PMID 36604431 · DOI 10.1038/s41392-022-01270-x
3. Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer.
   Picard E, Verschoor CP, Ma GW, Pawelec G. · · 2020 · cited 401× · PMID 32210966 · DOI 10.3389/fimmu.2020.00369
4. Immunotherapy in colorectal cancer: current achievements and future perspective.
   Fan A, Wang B, Wang X, Nie Y, et al · · 2021 · cited 321× · PMID 34671202 · DOI 10.7150/ijbs.64077
5. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside.
   Lizardo DY, Kuang C, Hao S, Yu J, et al · · 2020 · cited 160× · PMID 33035640 · DOI 10.1016/j.bbcan.2020.188447
6. Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials.
   Cohen R, Taieb J, Fiskum J, Yothers G, et al · · 2021 · cited 117× · PMID 33356421 · DOI 10.1200/jco.20.01600
7. Mismatch Repair-Deficient Colorectal Cancer: Building on Checkpoint Blockade.
   Jin Z, Sinicrope FA. · · 2022 · cited 112× · PMID 35649217 · DOI 10.1200/jco.21.02691
8. IFNγ signaling integrity in colorectal cancer immunity and immunotherapy.
   Du W, Frankel TL, Green M, Zou W. · · 2022 · cited 112× · PMID 34385592 · DOI 10.1038/s41423-021-00735-3