METIMMOX: Colorectal Cancer METastasis - Shaping Anti-tumor IMMunity by OXaliplatin

Hypothesis: Patients with MSS/pMMR-mCRC harbor tumor that can be transformed into an immunogenic disease by short-course oxaliplatin-based therapy, and may thereby benefit from the addition of immune-modulating therapy to improve outcome of the current oxaliplatin-based standard-of-care.

Primary objective: To determine progression-free survival (PFS), in terms of failure of treatment strategy, of sequential treatment with the Nordic FLOX (5-Fluorouracil, oxaliplatin and leucovorin) regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen in previously untreated MSS/pMMR-mCRC.

Secondary objectives: To determine safety and tolerability of sequential treatment with the Nordic FLOX regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen. To monitor and compare quality-of-life (QoL) alterations during therapy courses.

Inclusion criteria

• Patient has histologically verified CRC adenocarcinoma (also comprising the mucinous adenocarcinoma and signet-ring cell carcinoma entities).
• Patient is ambulatory with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Patient has radiologically measurable metastatic disease.
• Patient has an intra-abdominal metastatic lesion that can be biopsied.
• Patient has not had previous systemic therapy for the metastatic disease.
• Patient is eligible for the Nordic FLOX regimen.
• Patient has the following laboratory values, as measured in serum/plasma within 14 days prior to study entry, indicative of adequate organ function:

• Hemoglobin at least 10.0 g/dL.
• Neutrophils at least 1.5 x109/L (without current use of colony-stimulating factors).
• Platelets at least 100 x109/L.
• C-reactive protein (CRP) less than 60 mg/L.
• Aspartate transaminase (AST)/Alanine transaminase (ALT) no higher than 2xULN when patient does not have metastatic disease in the liver or no higher than 5xULN when patient has metastatic disease in the liver.
• Bilirubin no higher than 1.5x ULN when patient does not have metastatic disease in the liver or no higher than 2x upper limit of normal (ULN) when patient has metastatic disease in the liver.
• Albumin no lower than 30 g/L.
• International Normalised Ratio (INR) within normal level.
• Creatinine no higher than 1.5x ULN.
• Woman of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
• WOCBP will use an adequate method to avoid pregnancy for a period of 26 weeks (which includes the required 30 days plus the time required for nivolumab to undergo five half-lives) after the last therapy dose, irrespective of study arm.
• Woman is not breastfeeding.
• Male who is sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 26 weeks (which includes the required time to ensure duration of sperm turnover plus the time required for the investigational drugs to undergo five half-lives) after the last therapy dose, irrespective of study arm.
• Signed informed consent form (ICF) and expected cooperation of the patients for the treatment and follow-up must be obtained and documented according to International Conference on Harmonization (ICH) - Good Clinical Practice (GCP) and national/local regulations.

Exclusion criteria

• Patient has initially resectable metastatic disease for which neoadjuvant therapy is deemed superfluous.
• Patient does not consent to biopsy sampling.
• Patient has metastatic disease to lungs as the sole site.
• Patient has untreated or symptomatic brain metastasis (patient must be symptom-free without the use of corticosteroids).
• Patient experiences a period of less than 6 months since discontinuation of adjuvant oxaliplatin-containing chemotherapy.
• Patient is ineligible for full chemotherapy doses (100% doses) at start of study treatment.
• Patient has had radiation therapy against the only measurable lesion within 4 weeks of start of study treatment.
• Patient has any medical condition treated with anticoagulant medication that cannot be replaced by low molecular weight heparin during active study treatment.
• Patient has a nervous system disorder worse than Common Terminology Criteria for Adverse Events (CTCAE) grade 1.
• Patient has any medical condition that will preclude him/her from cancer immune-modulating therapy, such as:

• Active or chronic hepatitis B or hepatitis C.
• Known history of human immunodeficiency virus or acquired immunodeficiency-related illnesses.
• Diagnosis of immunodeficiency or medical condition requiring systemic steroids or other forms of immunosuppressive therapy.
• Autoimmune disease that has required systemic therapy within the past 2 years.
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study therapy.
• Active infection or chronic infection requiring chronic suppressive antibiotics.
• Known history of previous diagnosis of tuberculosis.
• Patient with current or prior use of immunosuppressive medication within 28 days before the first dose of study therapy, with the exceptions of intranasal corticosteroids or systemic corticosteroids at physiological doses that do not exceed 10mg/day of prednisone or an equivalent corticosteroid.
• Patient has any medical condition or needs to use medication, as listed in the Summary of Product characteristics (SmPC) of each Investigational Medical Product (IMP), that will preclude him/her from receiving treatment with IMP, such as:

• Pernicious anemia or anemias due to vitamin B12 deficiency (SmPC-listed contraindications for folinic acid).
• Other SmPC-listed contraindications for folinic acid and SmPC-listed contraindications for the other IMPs are covered by other exclusion criteria.
• Patient has undergone treatment with any IMP that may interfere with the study treatment within 4 weeks prior to first administration of study drug.
• Patient has known hypersensitivity to any of the study IMP components.
• Patient has ECOG performance status 2 or worse.
• Patient has serum/plasma CRP of 60 mg/L or higher.
• Patient does not meet the following requirements at baseline: adequate bone marrow function without current use of colony-stimulating factors (minimum values of neutrophils 1.5 x109/L, platelets 100 x109/L, hemoglobin 10 g/dL), adequate liver function (maximum values of AST/ALT 5x ULN and bilirubin 2x ULN; albumin value of 30 g/L or higher; INR within normal level), adequate renal function (maximum creatinine value of 1.5x ULN).
• Patient has history of other prior malignancy, with the exception of curatively treated basal cell or squamous cell carcinoma of the skin, cervical cancer stage IB ( clinically visible lesion confined to cervix uteri), stage I prostate cancer considered not necessary to treat, and another malignancy that was treated with curative intent more than 5 years ago and has not relapsed later.
• Patient has significant cardiac, pulmonary, or other medical illness that would limit activity of daily life or survival.
• Patient is pregnant or breastfeeding.
• Patient has any other reason, in the opinion of Clinical Investigator, not to participate in the study.