Later-line therapies after failure of standard treatments for metastatic colorectal cancer
patients are limited; regorafenib and TAS-102 have shown clinical activity for these
patients, however, efficacy outcomes seemed not to be sufficient although there have been
rather higher frequencies of adverse events.
Mismatch repair (MMR) deficiency or microsatellite instability-high (MSI-H) played a role of
negative predictive factor for adjuvant fluorouracil-based chemotherapy in patients with
resected colorectal cancer. In the metastatic setting, deficient MMR or MSI-H represented
poor prognosis; however, their predictive role has been documented after the pembrolizumab
trial was reported. The results of the pembrolizumab trial demonstrated that the PD-1
blockade with pembrolizumab monotherapy showed 40% of confirmed immune-related objective
response rates in patients with MMR deficient metastatic colorectal cancers; hence there was
no objective response in those with MMR proficient tumors. The progression-free rates at 20
weeks were 78% versus 11%, respectively, also favouring those with MMR deficient tumors.
However, the MMR deficiency of MSI-H is found in only about 5% in patients with metastatic
colorectal cancer, which is too small to expand potential candidate of immunotherapy.
One of the proposed mechanism of promising efficacy from pembrolizumab for MMR deficient
colorectal cancer is that MMR deficient or MSI-H colorectal cancers harbour higher somatic
mutation loads than MMR proficient colorectal cancer (a mean of 1782 somatic mutations per
tumor in the MMR deficient tumors versus 73 in the MMR proficient tumors in the results of
pembrolizumab trial); somatic mutations have the potential to encode non-self immunogenic
antigens; therefore, immunotherapy enhancing immune surveillance produced promising treatment
efficacy in the MMR deficient tumors.
The POLE gene encodes the catalytic subunit of DNA polymerase epsilon, and it involves DNA
repair and chromosomal replication. The POLE mutations are located in the exonuclease domain,
and their presence has already been reported in the various cancers including colorectal and
The POLE mutations represent high somatic mutation loads in patients with colorectal cancer,
especially in those with MMR proficient or MSS, therefore, tumors harbouring POLE mutations
might be susceptible to immune checkpoint blockade.
Based on these reasons, Investigator planned a phase II study of avelumab monotherapy in
patients with previously treated, metastatic, MMR deficient (MSI-H) or POLE mutated
1. Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum.
2. Mismatch repair deficient or microsatellite instable (defined below), or POLE mutated
tumors A. Mismatch repair deficient: loss of expression by immunohistochemical stains
4. ≥ 1 out of 4 markers (MLH1, MSH2, MSH6, PMS2) B. Microsatellite instable: loss of
stability ≥2 out of 5 gene panels (BAT-25, BAT-26, D2S123, D5S345, D17S250)
3. Progressed after at least first-line systemic chemotherapy for metastatic setting.
4. ≥ 1 measurable lesion(s) by RECIST 1.1.
5. Unresectable advanced or metastatic disease.
6. Age over 20 years old.
7. ECOG 0-1, but final decision by clinical.
8. Adequate organ functions. A. Bone marrow function: Hemoglobin 9.0 g/dL, ANC 1,500/mm3,
platelet 100,000/mm3 B. Hepatic functions: bilirubin ≤ 1.5 X ULN, AST/ALT ≤ 2.5 X ULN
(≤ 5 X ULN in cases of liver metastasis) C. Renal functions: serum Cr ≤ 1.5 X ULN or
calculated CCr (Cockroft) ≥ 30 ml/min
9. Be willing and able to comply with the protocol for the duration of the study.
10. Give written informed consent prior to study-specific screening procedures, with the
understanding that the patient has the right to withdraw the study at any time,
11. Female subjects must either be of non-reproductive potential ( 60 years old and no
menses for 1 year without an alternative medical cause, or history of hysterectomy, or
history of bilateral tubal ligation, or history of bilateral oophorectomy) or must
have a negative serum pregnancy test upon study entry.
12. Women of childbearing potential and men must agree to use highly efficient
contraception since signing of the IC form until at least 8 weeks after the last study
1. Any prior treatment with PD-1 or PD-L1 inhibitor.
2. Receipt of the last dose of chemotherapy ≤ 28 days prior to the first dose of study
3. Current or prior use of immunosuppressive medication within 28 days before the first
dose of avelumab, with the exceptions for the following: a. intranasal, inhaled,
topical steroids, or local steroid injection (e.g., intra-articular injection); b.
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent;
c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
4. Concurrent or previous history of another primary cancer within 3 years prior to
randomisation except for curatively treated cervical cancer in situ, non-melanomatous
skin cancer, superficial bladder cancer (pTis and pT1) and curatively treated thyroid
cancer of any stage. Concurrent, histologically confirmed, unresected thyroid cancer
without distant metastasis could be allowed with the agreement of the chief principal
5. Uncontrolled CNS metastases; permitted if asymptomatic or neurologically stable.
6. Prior radiation therapy would be permitted, but non-radiated evaluable lesions should
be present at study entry.
7. Radiation therapy during study treatment is not permitted, but if the local
investigator decides that radiation therapy should be given during study treatments,
he should be convinced that there is no evidence of disease progression with agreement
of the chief principal investigator.
8. 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
9. Active or prior documented autoimmune disease within the past 2 years; subjects with
diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring
immunosuppressive treatment are eligible.
10. Active or prior documented inflammatory bowel disease.
11. History of prior immunodeficiency.
12. History of allogeneic organ transplantation.
13. Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v4.03 Grade ≥ 3)
14. History of previous clinical diagnosis of active tuberculosis.
15. Vaccination within 4 weeks of the first dose of avelumab and while on trials is
prohibited except for administration of inactivated vaccines
16. Known history of testing positive for HIV
17. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
18. Major surgery or significant traumatic injury within 28 days prior to study treatment.
19. Non-healing wound, ulcer, or bone fracture.
20. Current evidence of significant gastrointestinal bleeding or (impending) obstruction.
21. Concomitant participation in another clinical trial.
22. Pregnant of breast-feeding subjects. Women of child-bearing potential must have
pregnancy test within 7 days and a negative result must be documented before start of
23. Substance abuse, medical, psychological or social conditions that may interfere with
the subject's participation in the study or evaluation of the study results.
24. Active infection requiring systemic therapy.
25. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however,
alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety
risk based on investigator's judgment are acceptable.
26. Other severe acute or chronic medical conditions including colitis, inflammatory bowel
disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent
(within the past year) or active suicidal ideation or behavior; or laboratory
abnormalities that may increase the risk associated with study participation or study
treatment administration or may interfere with the interpretation of study results
and, in the judgment of the investigator, would make the patient inappropriate for
entry into this study.