Clinical Trials /

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

NCT03827044

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.

Related Conditions:
  • Colon Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CCR 4673 POLEM
  • NCT ID: NCT03827044

Conditions

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

Interventions

DrugSynonymsArms
AvelumabBavencioAvelumab

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
AvelumabExperimental6 months of 2 weekly Avelumab
  • Avelumab
No interventionNo InterventionAfter standard adjuvant 5FU based chemotherapy, patients will have no active intervention but will start standard follow up.

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Male or female subjects aged ≥18 years
    
              2. ECOG PS 0/1
    
              3. 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).
    
              4. Fully surgically resected tumour with clear resection margins (i.e., >1 mm)
    
              5. 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)
    
              6. Absence of metastases as shown by post-operative CT scan
    
              7. 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)
    
            9. 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
    
            Exclusion Criteria:
    
              1. 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).
    
              2. Inability to start adjuvant chemotherapy within 12 weeks after surgery
    
              3. Administration of neoadjuvant systemic chemotherapy or radiotherapy before surgical
                 resection of colon cancer
    
              4. Prior organ transplantation, including allogeneic stem-cell transplantation
    
              5. 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
    
              6. 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
    
              7. 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)
    
              8. 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
    
              9. Pregnancy or lactation
    
             10. Known alcohol or drug abuse
    
             11. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
                 accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months
                 prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
                 Association Classification Class II), or serious cardiac arrhythmia requiring
                 medication
    
             12. Known history of colitis, pneumonitis and pulmonary fibrosis (for example,
                 inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the
                 Investigator, might impair the subject's tolerance of trial treatment.
    
             13. Any psychiatric condition that would prohibit the understanding or rendering of
                 informed consent
    
             14. Vaccination within 4 weeks of the first dose of Avelumab and while on trial is
                 prohibited except for administration of inactivated vaccines
    
             15. Other invasive malignancy within 2 years except for non-invasive malignancies such as
                 cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma
                 in situ of the breast that has/have been surgically cured. Cancer subjects with
                 incidental histological findings of prostate cancer (tumour/node/metastasis stage of
                 T1a or T1b or prostate-specific antigen ˂10) who have not received hormonal treatment
                 may be included, pending a discussion with the study physician.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Primary End point: Disease Free survival
    Time Frame:3 years
    Safety Issue:
    Description: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.

    Secondary Outcome Measures

    Measure:Secondary End Point: Overall Survival
    Time Frame:5 and 7 years
    Safety Issue:
    Description:Overall survival (OS) at 5 and 7 years. OS is measured from the date of randomisation to date of death from any cause.
    Measure:Secondary End Points: Quality of Life
    Time Frame:5 Years
    Safety Issue:
    Description:HRQoL according to the EuroQol EQ-5D-5L questionnaire at set time points.EQ-5D is designed for self-completion and as such captures information directly from the respondent, thereby generating data that conforms with the general requirement of all Patient Reported Outcome (PRO) measures.EQ-5D is designed for self-completion and as such captures information directly from the respondent, thereby generating data that conforms with the general requirement of all Patient Reported Outcome (PRO) measures.
    Measure:Secondary End Points: Toxicity of Investigational Medicinal Product
    Time Frame:5 Years
    Safety Issue:
    Description: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

    Details

    Phase:Phase 3
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Royal Marsden NHS Foundation Trust

    Trial Keywords

    • colon cancer
    • dMMR
    • POLE exonuclease domain mutant

    Last Updated