PHASE III RANDOMIZED STUDY OF FOLFOXIRI PLUS BEVACIZUMAB AND ATEZOLIZUMAB VERSUS FOLFOXIRI PLUS BEVACIZUMAB AS FIRST-LINE TREATMENT OF UNRESECTABLE pMMR AND IMMUNOSCORE IC-HIGH METASTATIC COLORECTAL CANCER PATIENTS. The AtezoTRIBE2 Study

Prior treatment

• Radiotherapy to any site within 4 weeks before the study;
• Uncontrolled hypertension (SBP>150 mmHg and/or DPB>100 mmHg), or prior history of hypertensive crisis, or hypertensive encephalopathy;
• Clinically significant (i.e., active) cardiovascular disease for example cerebrovascular accidents (within 6 months prior to study enrollment), myocardial infarction (within 6 months prior to study enrollment), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication;
• Any previous venous thromboembolism ≥ NCI CTCAE Grade 4;
• History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment;
• Current or recent (within 10 days prior to study treatment start) ongoing treatment with full-dose anticoagulants for therapeutic purposes. Note: Patients receiving prophylactic anticoagulants are eligible for this study;
• Previous adjuvant oxaliplatin-containing chemotherapy;
• Chronic, daily treatment with high-dose aspirin (>325 mg/day);
• Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer);
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study;
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of study treatment;
• Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last dose of bevacizumab, fluorouracil and within 5 months after the last dose of atezolizumab;
• Previous treatment with bevacizumab;
• Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) or hepatitis C;- Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti- HBc] antibody test) are eligible; - Note: Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA;
• Prior allogenic bone marrow transplantation or solid organ transplant;
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor [TNF] agents) within 2 weeks prior to start of study treatment, or requirement for systemic immunosuppressive medications during the trial. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed; - Note: Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study;
• Administration of a live, attenuated vaccine within 4 weeks prior to start of study treatment or anticipation that such a live attenuated vaccine will be required during the study;
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is longer, prior to start of study treatment;
• If receiving a RANKL inhibitor (e.g. denosumab), unwilling to adopt alternative treatment such as (but not limited to) bisphosphonates, while receiving atezolizumab.
• Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents;
• History of haemoptysis ≥ 2 grade NCIC-CTG criteria within one month prior to screening;

Other illness

• Serious, non-healing wound, ulcer, or bone fracture;
• Evidence of bleeding diathesis or coagulopathy;
• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment;
• Active infection requiring antibiotics at the time of initiation of study treatment;
• Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ;
• Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication;
• History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis; -Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study; - Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study;
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan; -Note: History of radiation pneumonitis in the radiation field (fibrosis) is permitted;
• Positive test for human immunodeficiency virus (HIV);
• Active tuberculosis;
• Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of the atezolizumab formulation;
• History or evidence upon physical examination of CNS disease unless adequately treated;
• Active or untreated CNS metastases. Patients with a history of treated asymptomatic CNS metastases are eligible provided they meet all the following criteria: -Measurable disease outside the CNS; - Only supratentorial or cerebellar metastases allowed (i.e., no metastases to midbrain, pons, medulla or spinal cord); - No ongoing requirement for corticosteroid therapy for CNS disease

Other

• Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria;
• Complete dihydropyrimidine dehydrogenase (DPYD) deficiency (homozygous of the following DPYD polymorphisms: c1679GG, c1905+1AA, c2846TT);
• Untreated brain metastases or spinal cord compression or primary brain tumours;

• Histologically proven diagnosis of colorectal cancer;
• Previous adjuvant chemotherapy allowed only if with fluoropyrimidine monotherapy and more than 6 months elapsed between the end of adjuvant and first relapse;
• Neutrophils >1.5 x 109/L, Platelets >100 x 109/L, Hb >9 g/dl;
• Total bilirubin ≤1.5 times the upper-normal limits (UNL) of the normal values and AST (SGOT) and/or ALT (SGPT) <2.5 x UNL (or <5 x UNL in case of liver metastases) alkaline phosphatase <2.5 x UNL (or <5 x UNL in case of liver metastases);
• Creatinine clearance ≥50 mL/min or serum creatinine ≤1.5 x UNL;
• INR or aPTT ≤1.5 x ULN. This applies only to patients who are not receiving therapeutic anticoagulation;
• Urine dipstick of proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate ≤1 g of protein/24 h;
• Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 continuous months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient;
• Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception) and outlined in “Section 6.5 – Contraception”, starting with the first dose of study therapy through 6 months after the last dose of bevacizumab and fluorouracil and within 5 months after the last dose of atezolizumab. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;
• Females of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 continuous months, are surgically sterile or sexually inactive;
• Will and ability to comply with the protocol;
• Initially unresectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease;
• Written informed consent to study procedures.
• Proficient mismatch repair (pMMR) status in tumour tissue (primary or metastatic), as determined by a local laboratory assay in a CLIA- or similarly certified;
• Immunoscore IC-high status in tumour tissue (primary or metastatic), as determined by a sponsor-defined central laboratory (HEGP, AP-HP, INSERM, France). Note: in case of metachronous disease, tumour tissue re-biopsy could be optionally performed only if it can be carried out safely with minimal risk and discomfort and patient’s disease is easily accessible. Fine-needle or cytological aspirates are not acceptable;
• At least one measurable lesion according to RECIST criteria (version 1.1);
• Availability of adequate tumour specimen (primary or metastatic);
• Male or female of 18-75 years of age;
• ECOG PS ≤ 2 if aged < 71 years, ECOG PS = 0 if aged 71-75 years;
• Life expectancy of at least 12 weeks;