| Eligibility |
Inclusion Criteria:
1. Signed written informed consent before any trial-related procedure is undertaken that
is not part of the standard patient management.
2. Male or female subjects aged = 18 years.
3. Histologically proven diagnosis of colorectal adenocarcinoma.
4. Diagnosis of metastatic disease.
5. RAS (NRAS and KRAS exon 2,3 and 4) and BRAF wild-type in liquid biopsy at screening
(according to NGS, Foundation/Roche).
6. Efficacy of a first line therapy containing cetuximab with a major response achieved
(i.e. complete or partial response according to RECIST criteria v1.1).
7. Received a second line therapy.
8. More than 4 months since the last dose of cetuximab administered in first line
treatment before randomization.
9. Measurable disease according to RECIST criteria v1.1.
10. ECOG PS of 0 to 1 at trial entry.
11. Estimated life expectancy of more than 12 weeks.
12. Adequate hematological function defined by white blood cell (WBC) count = 2.5 × 109/L
with absolute neutrophil count (ANC) = 1.5 × 109/L, lymphocyte count = 0.5 × 109/L,
platelet count = 100 × 109/L, and hemoglobin = 9 g/dL (may have been transfused).
13. Adequate hepatic function defined by a total bilirubin level = 1.5 × the upper limit
of normal (ULN) range and AST and alanine aminotransferase (ALT) levels = 2.5 × ULN
for all subjects or AST and ALT levels = 5 x ULN (for subjects with documented
metastatic disease to the liver).
14. Adequate renal function defined by an estimated creatinine clearance > 30 mL/min
according to the Cockcroft-Gault formula (or local institutional standard method).
15. Effective contraception for both male and female subjects throughout the study and for
at least 2 months after last study treatment administration if the risk of conception
exists (Note: The effects of the trial drug on the developing human fetus are unknown;
thus, women of childbearing potential and men must agree to use effective
contraception, defined as 2 barrier methods, or 1 barrier method with a spermicide, an
intrauterine device, or use of oral female contraceptive. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
trial, the treating physician should be informed immediately).
16. No prior immunotherapy
Exclusion Criteria:
1. Any contraindication to cetuximab and/or avelumab.
2. Past or current history of malignancies other than colorectal carcinoma, except for
curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma
of the cervix.
3. Pregnancy.
4. Breastfeeding.
5. Participation in a clinical study or experimental drug treatment within 30 days before
enrollment.
6. Subjects receiving immunosuppressive agents (such as steroids) for any reason, should
be tapered off these drugs before initiation of the trial treatment, with the
exception of:
- Subjects with adrenal insufficiency, who may continue corticosteroids at
physiologic replacement dose, equivalent to = 10 mg prednisone daily
- Intranasal, inhaled, topical steroids,
- Local steroid injection (e.g., intra-articular injection)
- Systemic corticosteroids at physiologic doses = 10 mg/day of prednisone or
equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
7. All subjects with brain metastases, except those meeting the following criteria:
- Brain metastases have been treated locally
- No ongoing neurological symptoms related to the brain localization of the disease
(sequelae that are a consequence of the treatment of the brain metastases are
acceptable)
8. Prior organ transplantation, including allogeneic stemcell transplantation
9. Significant acute or chronic infections including, among others:
- Known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome
- 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)
10. 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
steroids are administered only for the purpose of hormonal replacement and at
doses = 10 mg or equivalent prednisone per day.
- Administration of steroids through a route known to result in a minimal systemic
exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
- Active infection requiring systemic therapy.
11. Previous or ongoing administration of systemic steroids for the management of an acute
allergic phenomenon is acceptable as long as it is anticipated that the administration
of steroids will be completed in 14 days, or that the daily dose after 14 days will be
= 10 mg per day of equivalent prednisone.
12. Known severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v 5 Grade = 3), any history of anaphylaxis, or uncontrolled
asthma (that is, 3 or more features of partially controlled asthma).
13. History of hypersensitivity to Polysorbate 80 that led to unacceptable toxicity
requiring treatment cessation.
14. Persisting toxicity related to prior therapy of Grade > 1 NCI- CTCAE v 5.0.
15. Known alcohol or drug abuse.
16. Clinically significant (that is 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 uncontrolled cardiac arrhythmia
requiring medication.
17. History of keratitis, ulcerative keratitis or severe dry eye. Since contact lent use
is also a risk factor for keratitis and ulceration, it is not recommended.
18. Other severe acute or chronic medical conditions including immune colitis,
inflammatory bowel disease, immune 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.
19. Vaccination within 4 weeks of the first dose of avelumab and cetuximab and while on
treatment is prohibited except for administration of inactivated vaccine (i.e.
inactivated influenza vaccine)
20. Legal incapacity or limited legal capacity.
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