ICE Study: Combination of Irinotecan Plus Cetuximab and Envafolimab as a Rechallenge Regimen in mCRC

Inclusion Criteria:

• Signed written informed consent before any trial-related procedure is undertaken thatis not part of the standard patient management. Male or female subjects aged ≥ 18 years. Histologically proven diagnosis of colorectaladenocarcinoma. Diagnosis of metastatic disease. RAS (NRAS and KRAS exon 2,3 and 4) andBRAF wild-type in liquid biopsy at screening (according to NGS) Efficacy of any front-linetherapies containing cetuximab or irinotecan with a major response achieved (i.e. completeor partial response according to RECIST criteria v1.1).. More than 2 months since the last dose of cetuximab administered in first line treatmentbefore randomization. Measurable disease according to RECIST criteria v1.1. ECOG PS of 0 to 1 at trial entry.Estimated life expectancy of more than 12 weeks. Adequate hematological function defined bywhite 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 ≥ 9g/dL (may have been transfused). Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit ofnormal (ULN) range and AST and alanine aminotransferase (ALT) levels ≤ 2.5 × ULN for allsubjects or AST and ALT levels ≤ 5 x ULN (for subjects with documented metastatic diseaseto the liver). Adequate renal function defined by an estimated creatinine clearance > 30 mL/min accordingto the Cockcroft-Gault formula (or local institutional standard method). Effective contraception for both male and female subjects throughout the study and for atleast 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, womenof childbearing potential and men must agree to use effective contraception, defined as 2barrier methods, or 1 barrier method with a spermicide, an intrauterine device, or use oforal female contraceptive. Should a woman become pregnant or suspect she is pregnant whileshe or her partner is participating in this trial, the treating physician should beinformed immediately).

Exclusion Criteria:

• Any contraindication to cetuximab and/or envafolimab. Past or current history ofmalignancies other than colorectal carcinoma, except for curatively treated basal andsquamous cell carcinoma of the skin or in situ carcinoma of the cervix. Pregnancy. Breastfeeding. Participation in a clinical study or experimental drug treatmentwithin 30 days before enrollment. Subjects receiving immunosuppressive agents (such as steroids) for any reason, should betapered off these drugs before initiation of the trial treatment, with the exception of: Subjects with adrenal insufficiency, who may continue corticosteroids at physiologicreplacement dose, equivalent to ≤ 10 mg prednisone daily Intranasal, inhaled, topicalsteroids, Local steroid injection (e.g., intra-articular injection) Systemiccorticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent Steroids aspremedication for hypersensitivity reactions (e.g., CT scan premedication) No ongoingneurological symptoms related to the brain localization of the disease (sequelae that are aconsequence of the treatment of the brain metastases are acceptable) Prior organtransplantation, including allogeneic stemcell transplantation Significant acute or chronic infections including, among others: Known history of positive test for human immunodeficiency virus (HIV) or known acquiredimmunodeficiency syndrome Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease notrequiring immunosuppressive treatment are eligible. Subjects requiring hormone replacement with corticosteroids are eligible if steroids areadministered only for the purpose of hormonal replacement and at doses ≤ 10 mg orequivalent 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. Previous or ongoing administration of systemicsteroids for the management of an acute allergic phenomenon is acceptable as long as it isanticipated that the administration of steroids will be completed in 14 days, or that thedaily dose after 14 days will be ≤ 10 mg per day of equivalent prednisone. Known severe hypersensitivity to investigational product or any component in itsformulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v 5 Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma (that is, 3or more features of partially controlled asthma). History of hypersensitivity to Polysorbate 80 that led to unacceptable toxicity requiringtreatment cessation. Persisting toxicity related to prior therapy of Grade > 1 NCI- CTCAE v 5.0. Known alcoholor drug abuse. Clinically significant (that is active) cardiovascular disease: cerebralvascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 monthsprior to enrollment), unstable angina, congestive heart failure (New York Heart AssociationClassification Class ≥ II), or serious uncontrolled cardiac arrhythmia requiringmedication. History of keratitis, ulcerative keratitis or severe dry eye. Since contact lent use isalso a risk factor for keratitis and ulceration, it is not recommended. Other severe acute or chronic medical conditions including immune colitis, inflammatorybowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions includingrecent (within the past year) or active suicidal ideation or behavior; or laboratoryabnormalities that may increase the risk associated with study participation or studytreatment administration or may interfere with the interpretation of study results and, inthe judgment of the investigator, would make the patient inappropriate for entry into thisstudy. Legal incapacity or limited legal capacity.