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

NCT03827044 | Terminated Phase 3 DMC FDA Drug

• 1 other identifier: CCR 4673 POLEM
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

POLE Exonuclease Mutant Colon Cancer; Microsatellite Instability; Stage III Colon Cancer

Keywords

colon cancer; dMMR; POLE exonuclease domain mutant

Outcome Measures

Primary Outcomes (1)

• Primary End point: Disease Free survival

  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.

  3 years

Secondary Outcomes (3)

• Secondary End Point: Overall Survival

  5 and 7 years

• Secondary End Points: Quality of Life

  5 Years

• Secondary End Points: Toxicity of Investigational Medicinal Product according to the NCI-CTCAE (Common Terminology Criteria for Adverse Events) version 4.0.

  5 Years

Study Arms (2)

Avelumab

EXPERIMENTAL

6 months of 2 weekly Avelumab

Drug: Avelumab

No intervention

NO INTERVENTION

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

Interventions

Avelumab DRUG

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.

Also known as: Bavencio

Avelumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female subjects aged ≥18 years
• ECOG PS 0/1
• Histologically proven, stage III (i.e., any T, N1 or N2, M0) adenocarcinoma of the colon (as defined by the presence of the inferior pole of the tumour above the peritoneal reflection - that is, at least 15 cm from the anal margin).
• Fully surgically resected tumour with clear resection margins (i.e., \>1 mm)
• Locally confirmed defective mismatch repair (dMMR) tumour (as defined by the lack of staining on either the pre-operative biopsy samples or resection specimens of at least one of the following proteins: MLH1 (mutL homolog 1), MSH2 (mutS homologue 2), MSH6 (mutS homolog 6), PMS2 or centrally confirmed POLE exonuclease domain mutated tumour (in subjects \<50 years old with pMMR tumours)
• Absence of metastases as shown by post-operative CT scan
• Absence of major post-operative complications or other clinical conditions that, in the opinion of the investigator, would contraindicate adjuvant chemotherapy 8. Adequate hematological function defined by absolute neutrophil count (ANC) ≥1.5 × 109/L, platelet count ≥100 × 109/L, and hemoglobin ≥9 g/dL (blood transfusion before recruitment is allowed)
• \. Adequate hepatic function defined by a total bilirubin level ≤1.5 × the upper limit of normal (ULN) range and AST and ALT levels ≤2.5 × ULN 10. Adequate renal function defined by an estimated creatinine clearance ≥30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) 11. Negative serum or urine pregnancy test at screening for women of childbearing potential 12. Fertile men and women must agree to take highly effective contraceptive precautions during, and for 6 months after the last dose of chemotherapy or for 1 month after the last dose of Avelumab

You may not qualify if:

• Rectal tumours (as defined by the presence of the inferior pole of the tumour below the peritoneal reflection - that is, \<15 cm from the anal margin).
• Inability to start adjuvant chemotherapy within 12 weeks after surgery
• Administration of neoadjuvant systemic chemotherapy or radiotherapy before surgical resection of colon cancer
• Prior organ transplantation, including allogeneic stem-cell transplantation
• Significant acute or chronic infections including, among others:
• known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• positive test for HBV (Hepatitis B) surface antigen or anti-HCV (Hepatitis C) antibody and confirmatory HCV RNA test
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
• Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
• Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤10 mg/day of prednisone or equivalent
• Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
• Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3 NCI-CTCAE v4.0), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
• Persisting toxicity related to prior therapy of Grade \>1 NCI-CTCAE v4.0; however, alopecia and sensory neuropathy Grade ≤2 is acceptable unless oxaliplatin administration is planned as part of the adjuvant treatment
• Pregnancy or lactation
• Known alcohol or drug abuse

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• University of Surrey: collaborator
• University of Oxford: collaborator
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (1)

Royal Marsden NHS Foundation Trust

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Lau D, Kalaitzaki E, Church DN, Pandha H, Tomlinson I, Annels N, Gerlinger M, Sclafani F, Smith G, Begum R, Crux R, Gillbanks A, Wordsworth S, Chau I, Starling N, Cunningham D, Dhillon T. Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study. ESMO Open. 2020 Feb;5(1):e000638. doi: 10.1136/esmoopen-2019-000638.

  PMID: 32079623 DERIVED

MeSH Terms

Conditions

Microsatellite Instability; Colonic Neoplasms

Interventions

avelumab

Condition Hierarchy (Ancestors)

Genomic Instability; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases

Study Officials

• Tony Dhillon, Bsc,FRCP, PhD

  University of Surrey

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 26, 2018
• First Posted: February 1, 2019
• Study Start: August 31, 2018
• Primary Completion: January 5, 2021
• Study Completion: January 5, 2022
• Last Updated: October 7, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)