AVELUMAB and CETUXIMAB and mFOLFOXIRI as Initial Therapy for Unresectable Metastatic Colorectal Cancer Patients

Inclusion Criteria:

• Histologically proven diagnosis of colorectal adenocarcinoma;

• Initially unresectable metastatic colorectal cancer not previously treated withchemotherapy for metastatic disease;

• At least one measurable lesion according to RECIST 1.1.;

• Availability of a tumour tissue sample (primary tumour and/or metastatic sites);

• Male or female of 18-75 years of age;

• ECOG PS ≤2 for patients aged ≤70 years; ECOG PS 0 for patients aged 71 to 75 years;

• Life expectancy of at least 12 weeks;

• Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy andmore than 6 months elapsed between the end of adjuvant and first relapse;

• RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) wild-type status ofprimary colorectal cancer or related metastasis (local or central laboratoryassessment);

• Adequate haematological function: neutrophils >1.5 x 109/L, platelets >100 x 109/L,haemoglobin >9 g/dl;

• Adequate liver and renal function: total bilirubin 1.5 time the upper-normal limits (UNL) of the normal values and AST (SGOT) and/or ALT (SGPT) <2.5 x UNL (or <5 x UNLin case of liver metastases) alkaline phosphatase <2.5 x UNL (or <5 x UNL in case ofliver metastases); creatinine clearance ≥50 mL/min or serum creatinine 1.5 x UNL;

• INR or aPTT ≤1.5 × ULN. Patients who are on therapeutic doses of anti-coagulants areeligible if they are on a stable dose of anti-coagulant for 28 days with stable INRand PTT values;

• Women of childbearing potential must have a negative blood pregnancy test at thebaseline visit. For this trial, women of childbearing potential are defined as allwomen after puberty, unless they are postmenopausal for at least 12 continuousmonths, are surgically sterile, or are sexually inactive;

• Subjects and their partners must be willing to avoid pregnancy during the trial anduntil 6 months after the last trial treatment. Male subjects with female partners ofchildbearing potential and female subjects of childbearing potential must,therefore, be willing to use adequate contraception as approved by the investigator (barriere contraceptive measure or oral contraception);

• Will and ability to comply with the protocol;

• Written informed consent to study procedures and to molecular analyses.

Exclusion Criteria:

• Radiotherapy to any site within 4 weeks before the study;

• Previous adjuvant oxaliplatin-containing chemotherapy;

• Previous treatment with cetuximab;

• Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1therapeutic antibody or pathway-targeting agents;

• Treatment with any investigational drug within 30 days prior to enrollment or 2investigational agent half-lives (whichever is longer);

• Major surgery for any reason, except diagnostic biopsy, within 4 weeks of the trialtreatment and/or if the subject has not fully recovered from the surgery within 4weeks of the trial treatment, or anticipation of the need for major surgicalprocedure during the course of the study;

• 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 corticosteroidsat physiologic replacement dose, equivalent to < 10 mg prednisone daily).

Notes:

1. Subjects receiving bisphosphonate or denosumab are eligible provided treatment wasinitiated at least 14 days before first dose of trial treatment;

2. Previous or ongoing administration of systemic steroids for the management of anacute allergic phenomenon is acceptable as long as it is anticipated that theadministration of steroids will be completed in 14 days, or that the daily doseafter 14 days will be ≤ 10 mg per day of equivalent prednisone.

• All subjects with brain metastases, except those meeting the followingcriteria:

a. Brain metastases have been treated locally, have not been progressing at least 2 months after completion of therapy, and no steroid maintenance therapy is required, and b. No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable).

• Symptomatic peripheral neuropathy > 2 grade NCI-CTCAE v5.0;

• Other co-existing malignancies or previous malignant disease (other than colorectalcancer) within the last 5 years with the exception of basal or squamous cellcarcinoma of the skin or carcinoma in situ (bladder, cervical, breast);

• Prior organ transplantation, including allogeneic stem cell transplantation;

• Significant acute or chronic infections, including, among others:

1. Known history of testing positive for human immunodeficiency virus or knownacquired immunodeficiency syndrome;

2. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to registration) or hepatitis C. Notes: Patients with pasthepatitis B virus (HBV) infection or resolved HBV infection (defined as havinga negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negativefor HCV RNA.

3. Active tuberculosis (history of exposure or history of positive TB test; pluspresence of clinical symptoms, physical or radiographic findings).

• Active autoimmune disease, including but not limited to myasthenia gravis, myositis,autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,inflammatory bowel disease, vascular thrombosis associated with antiphospholipidsyndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,multiple sclerosis, vasculitis, or glomerulonephritis, that might deteriorate whenreceiving an immunostimulatory agent:

1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- and hyperthyroiddisease not requiring immunosuppressive treatment are eligible;

2. History of autoimmune-related hypothyroidism on a stable dose of thyroidreplacement hormone may be eligible for this study;

3. History of controlled type I diabetes mellitus on a stable insulin regimen maybe eligible for this study;

4. Subjects requiring hormone replacement with corticosteroids are eligible if thesteroids are administered only for the purpose of hormonal replacement and atdose ≤ 10 mg or 10 mg equivalent prednisone per day;

5. Administration of steroids through a route known to result in minimal systemicexposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.

• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-inducedpneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenicorganizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.Note: History of radiation pneumonitis in the radiation field (fibrosis) ispermitted;

• Known prior severe hypersensitivity to investigational product or any component inits formulations, including known severe hypersensitivity reactions to moAbs (NCICTCAE v5.0 Grade ≥ 3), any history or anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma);

• Pregnant or lactating women. Women of childbearing potential with either a positiveor no pregnancy test at baseline. Postmenopausal women must have been amenorrheicfor at least 12 months to be considered of non-childbearing potential.

Sexually active males and females (of childbearing potential) unwilling to practice contraception (barriere contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.

• Known alcohol or drug abuse;

• History of uncontrolled intercurrent illness included but not limited to:

1. Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHgor lower);

2. or, uncontrolled active infection requiring antibiotics at the time ofinitiation of study treatment.

• Clinically significant (i.e., active) cardiovascular disease for examplecerebrovascular accidents (≤6 months), transient ischemic attack, myocardialinfarction (≤6 months), severe/unstable angina, coronary/peripheral artery bypassgraft, New York Heart Association (NYHA) grade II or greater congestive heartfailure, serious cardiac arrhythmia requiring medication (including correct QTinterval [QTc] prolongation of > 470 msec calculated according to Fridericia and/orpacemaker or prior diagnosis of congenital long QT syndrome), or symptomaticpulmonary embolism;

• Uncontrolled coagulopathy;

• Lack of upper gastrointestinal tract integrity or malabsorption syndrome; activeinflammatory bowel disease (i.e., patients requiring current medical interventionsor who are symptomatic).

• All other significant disease which, in the opinion of the Investigator, mightimpair the subject's tolerance of trial treatment;

• Any psychiatric condition that would prohibit the understanding or rendering ofinformed consent and that would limit compliance with trial requirements;

• Administration of a live, attenuated vaccine within 4 weeks prior to start of studytreatment or anticipation that such a live attenuated vaccine will be requiredduring the study. Note: administration of inactivated vaccines is allowed (forexample, inactivated influenza vaccines);

• Treatment with systemic corticosteroids or other systemic immunosuppressivemedications (including but not limited to prednisone, dexamethasone,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosisfactor [TNF] agents) within 2 weeks prior to start of study treatment, orrequirement for systemic immunosuppressive medications during the trial. The use ofinhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed;

• Treatment with systemic immunostimulatory agents (including but not limited tointerferons or interleukin-2) within 4 weeks or five half-lives of the drug,whichever is longer, prior to start of study treatment;

• Legal incapacity or limited legal capacity.