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.
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
Drug | Synonyms | Arms |
---|
Avelumab | Bavencio | Avelumab |
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
Name | Type | Description | Interventions |
---|
Avelumab | Experimental | 6 months of 2 weekly Avelumab | |
No intervention | No Intervention | After 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: | 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) |
Measure: | Secondary End Points: Toxicity of Investigational Medicinal Product according to the NCI-CTCAE (Common Terminology Criteria for Adverse Events) version 4.0. |
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: | Active, not recruiting |
Lead Sponsor: | Royal Marsden NHS Foundation Trust |
Trial Keywords
- colon cancer
- dMMR
- POLE exonuclease domain mutant
Last Updated
July 13, 2021