CAVE-2 GOIM Study: a Clinical Study of the Combination of Avelumab Plus Cetuximab as Rechallenge Strategy

Inclusion Criteria:

1. Signed written informed consent before any trial-related procedure is undertaken thatis 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 linetreatment 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/Lwith 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 limitof normal (ULN) range and AST and alanine aminotransferase (ALT) levels ≤ 2.5 × ULNfor all subjects or AST and ALT levels ≤ 5 x ULN (for subjects with documentedmetastatic disease to the liver).
14. Adequate renal function defined by an estimated creatinine clearance > 30 mL/minaccording to the Cockcroft-Gault formula (or local institutional standard method).
15. Effective contraception for both male and female subjects throughout the study and forat least 2 months after last study treatment administration if the risk of conceptionexists (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 effectivecontraception, defined as 2 barrier methods, or 1 barrier method with a spermicide, anintrauterine device, or use of oral female contraceptive. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating in thistrial, 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 forcuratively treated basal and squamous cell carcinoma of the skin or in situ carcinomaof the cervix.
3. Pregnancy.
4. Breastfeeding.
5. Participation in a clinical study or experimental drug treatment within 30 days beforeenrollment.
6. Subjects receiving immunosuppressive agents (such as steroids) for any reason, shouldbe tapered off these drugs before initiation of the trial treatment, with theexception of:

• Subjects with adrenal insufficiency, who may continue corticosteroids atphysiologic 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 orequivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

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 areacceptable)

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 knownacquired 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 testpositive)

10. Active autoimmune disease that might deteriorate when receiving an immunostimulatoryagent:

• Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid diseasenot requiring immunosuppressive treatment are eligible.
• Subjects requiring hormone replacement with corticosteroids are eligible ifsteroids are administered only for the purpose of hormonal replacement and atdoses ≤ 10 mg or equivalent prednisone per day.
• Administration of steroids through a route known to result in a minimal systemicexposure (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 acuteallergic phenomenon is acceptable as long as it is anticipated that the administrationof 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 itsformulations, including known severe hypersensitivity reactions to monoclonalantibodies (NCI CTCAE v 5 Grade ≥ 3), any history of anaphylaxis, or uncontrolledasthma (that is, 3 or more features of partially controlled asthma).
13. History of hypersensitivity to Polysorbate 80 that led to unacceptable toxicityrequiring 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 vascularaccident/stroke (<6 months prior to enrollment), myocardial infarction (<6 monthsprior to enrollment), unstable angina, congestive heart failure (New York HeartAssociation Classification Class ≥ II), or serious uncontrolled cardiac arrhythmiarequiring medication.
17. History of keratitis, ulcerative keratitis or severe dry eye. Since contact lent useis 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 psychiatricconditions including recent (within the past year) or active suicidal ideation orbehavior; or laboratory abnormalities that may increase the risk associated with studyparticipation or study treatment administration or may interfere with theinterpretation of study results and, in the judgment of the investigator, would makethe patient inappropriate for entry into this study.
19. Vaccination within 4 weeks of the first dose of avelumab and cetuximab and while ontreatment is prohibited except for administration of inactivated vaccine (i.e.inactivated influenza vaccine)
20. Legal incapacity or limited legal capacity.