Colorectal Cancer MetastaticPhase 2METIMMOXNCT03388190

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

A Phase 2 study testing Nivolumab and FLOX in people with Colorectal Cancer Metastatic, run by University Hospital, Akershus at 5 sites in Norway.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

This study aims to determine the efficacy, safety, and tolerability of the sequential addition of immune-modulating therapy to standard-of-care therapy of microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) metastatic colorectal cancer (mCRC). Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Colorectal Cancer Metastatic
What is being tested?: Nivolumab and FLOX
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 80 participants
Where: 5 sitesNorway
Study dates: 29 May 2018to 18 Mar 2024
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

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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.

Who cannot join

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.

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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.

Trial locations and contacts

5 sites in 1 country.

City, postcode or hospital

5 sites in 1 country

Norway5 sites

Haukeland University Hospital
Bergen, 5021
Hospital of Southern Norway, Department of Oncology
Kristiansand, 4604
Oslo University Hospital
Oslo, 0424
Akershus University Hospital
Oslo, 1478
St Olav's Hospital - Trondheim University Hospital
Trondheim, 7006

Other trials in Norway

About this study

Read the detailed description

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.

Conditions: Colorectal Cancer Metastatic
Being tested: Nivolumab, FLOX
Keywords: Colorectal, Cancer, Neoplasm, Nivolumab, Fluorouracil, Metastatic, Oxaliplatin, Leucovorin
Medical subject headings: Neoplasms, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

NivolumabDrug
Also called Oxaliplatin, 5-fluorouracil, Leucovorin
FLOX: Intravenous oxaliplatin 85 mg/m2 on day 1; bolus 5-fluorouracil 500 mg/m2 and bolus Leucovorin on days 1 and 2; IV administration every 2 weeks.
Nivolumab: 240 mg flat dose; IV administration every 2 weeks.
FLOXDrug
Also called Oxaliplatin, 5-fluorouracil, Leucovorin
FLOX: Intravenous oxaliplatin 85 mg/m2 on day 1; bolus 5-fluorouracil 500 mg/m2 and bolus Leucovorin on days 1 and 2; IV administration every 2 weeks.

Study groups in NCT03388190
Study group	Role	What they receive
Control Arm	Active comparator	The control arm will consist of intermittent treatment with the Nordic FLOX regimen in terms of 8 cycles before break until disease progression, when therapy is reintroduced and administered for another 8 cycles before a new break. This schedule will be continued until progressive disease on ongoing therapy (PFS), intolerable toxicity, withdrawal of consent, or death, whichever occurs first. Receives: Drug: FLOX
Experimental Arm	Experimental	The experimental arm will consist of repeat 2 cycles of the Nordic FLOX regimen followed by 2 cycles of nivolumab for a total of 8 individual cycles before break until disease progression, when therapy is reintroduced and administered for another total of 8 individual cycles before a new break. This schedule will be continued until progressive disease on ongoing therapy (PFS), intolerable toxicity, withdrawal of consent, or death, whichever occurs first. Receives: Drug: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

Primary - Progression-free Survival (PFS)
To determine PFS, in terms of failure of treatment strategy, on sequential treatment with the Nordic FLOX regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen in previously untreated MSS mCRC.
*PFS: radiologic assessment every 8 weeks (following 4 cycles of FLOX or the alternative 2 cycles each of FLOX and nivolumab), according to the Response Evaluation Criteria in Solid Tumors (RECIST) and the RECIST consensus guideline for assessment of response to immune-modulating therapies (iRECIST), wherein complete response = disappearance of the lesion, partial response = at least a 30% decrease in the sum of diameters of target lesions, progressive disease = at least 20% increase in the sum of diameters of target lesions, and stable disease = no shrinkage or increase in size (per Watanabe H, Okada M, Kaji Y, et al. Gan To Kagaku Ryoho. 2009;36(13):2495-2501).
Measured: Through study completion (up to 37 months)

Secondary outcomes (8)

Secondary 1 - Incidence (Safety) and Grading (Tolerability) of Treatment-related Adverse Events
To determine the number of participants (incidence; safety) with treatment-related adverse events and their grading (tolerability), as assessed by CTCAE v4.0, of sequential treatment with the Nordic FLOX regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen. A lower adverse event score is better, where a score of 0 is best (no adverse event), 3 is severe, and 5 is death caused by the treatment. Stage 2 adverse events were not specifically reported unless related to hepatic toxicity events due to the potential effects of the drug on the patient (safety profile).
Measured: Through study completion (up to 37 months)
Secondary 2 - Objective Response Rate (ORR)
To determine the percentage of patients with confirmed complete or partial response of sequential treatment with the Nordic FLOX regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen.
Measured: Through study completion (up to 37 months)
Secondary 3 - Duration of Response (DOR)
To determine the time from the first documentation of a complete or partial response to disease progression of sequential treatment with the Nordic FLOX regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen.
Measured: Through study completion (up to 37 months)
Secondary 4 - Secondary Curative Resection Rate (SSCRR)
To determine the percentage of patients with a confirmed resection of metastatic disease with microscopically free margin (R0) of sequential treatment with the Nordic FLOX regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen.
Measured: Through study completion (up to 37 months)
Secondary 5 - Overall Survival (OS)
To determine the time from randomization to death of any cause of sequential treatment with the Nordic FLOX regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen.
Measured: Through study completion (up to 37 months)
Secondary 6 - Quality-of-life (QoL)
To monitor and compare QoL alterations during therapy courses using the consensus module EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life, 30 question version).
The (patient-reported) EORTC-QLQ-C30 uses 5 functional scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea and vomiting), a global health status/quality of life scale and a number of other questions which assess items such as dyspnoea, loss of appetite, insomnia, constipation and diarrhoea, as well as the perceived financial impact of having cancer. Scales range from 0 to 100, and a higher score means a higher response rate, where a high score on the functional or global health status questions represents a high or healthy level of functioning, quality of life or, alternatively, more symptoms or issues (symptom scale/items). [Scoring information summarised from the EORTC QLQ-C30 Scoring manual, 3rd edition]
Measured: Through study completion (up to 37 months)
Secondary 7 - Quality-of-life (QoL)
To monitor and compare QoL alterations during therapy courses using the consensus module EORTC QLQ-CIPN20 (European Organisation for Research and Treatment of Cancer Quality of Life, 20 question Chemotherapy Induced Peripheral Neuropathy questionnaire).
The EORTC QLQ-CIPN20 uses 20 questions assessing the quality of sensory, motor and autonomic symptoms on a 4-point Likert scale. Answers range from 1 (not at all) to 4 (very much). Patients indicate their perception of each item, and the scores are aggregated by quality, with a maximum of 32 points for motor, 36 for sensory, and either 12 (men) or 8 (women) in autonomic, where women would not answer a question about erectile function. Scores are then added together to give an overall score. The higher the score, the more symptoms the patient is experiencing.
Measured: Through study completion (up to 37 months)
Secondary 8 - Quality-of-life (QoL)
To monitor and compare QoL alterations during therapy courses using the consensus module EQ-5D-5L (EuroQoL's 5-dimension, 5-level questionnaire).
The EQ-5D-5L questionnaire is a "standardised measure of health status developed by the EuroQol group to provide a simple, generic measure of health for clinical and economic appraisal". The questionnaire uses 5 dimensions (5D) - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. There are 5 response levels: no issues, slight problems, moderate problems, severe problems and unable to function/extreme problems. These answers are geared appropriately to the specific question being asked. Responses are coded from 0 for no problems to 5 for unable to function, and are combined to give a 5-digit code that will describe the patient's state of health. For example, 21111 would mean slight problems with mobility, but no other issues in the other dimensions. (summarised from the EQ-5D-5L user guide, v3.0).
Measured: Through study completion (up to 37 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

29 May 201818 Mar 2024

First posted2 Jan 2018
Study start29 May 2018
Primary completion18 Mar 2024
Study completion18 Mar 2024

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (14)Papers the sponsor has linked to this study.
Other trials for Colorectal Cancer MetastaticStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Model description: The METIMMOX study is a multicenter open-label randomized phase 2 trial in first-line treatment of MSS/pMMR-mCRC using the standard-of-care Nordic FLOX regimen (control arm) or sequential therapy with the Nordic FLOX regimen and nivolumab (experimental arm), to investigate whether the experimental arm shows superiority in PFS, safety, tolerability, and QoL.
Masking: None (open label)
Enrolment: 80 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03388190
Sponsor's protocol ID: CA209-9M8
Other IDs: 2017-001845-29, 2017
Acronym: METIMMOX
Status last verified: Jan 2026
First submitted: 8 Dec 2017
Last updated: 13 Feb 2026
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No: No plan to share unrandomised, individual participant data with any researchers not involved in the study at the outset.

Publications

Dueland S, Ree AH, Groholt KK, Saelen MG, Folkvord S, Hole KH, Seierstad T, Larsen SG, Giercksky KE, Wiig JN, Boye K, Flatmark K. Oxaliplatin-containing Preoperative Therapy in Locally Advanced Rectal Cancer: Local Response, Toxicity and Long-term Outcome. Clin Oncol (R Coll Radiol). 2016 Aug;28(8):532-9. doi: 10.1016/j.clon.2016.01.014. Epub 2016 Feb 14.
PubMed 26888115
Flatmark K, Saelen MG, Hole KH, Abrahamsen TW, Fleten KG, Hektoen HH, Redalen KR, Seierstad T, Dueland S, Ree AH. Individual tumor volume responses to short-course oxaliplatin-containing induction chemotherapy in locally advanced rectal cancer - Targeting the tumor for radiation sensitivity? Radiother Oncol. 2016 Jun;119(3):505-11. doi: 10.1016/j.radonc.2016.02.020. Epub 2016 Mar 8.
PubMed 26968754
Grovik E, Redalen KR, Storas TH, Negard A, Holmedal SH, Ree AH, Meltzer S, Bjornerud A, Gjesdal KI. Dynamic multi-echo DCE- and DSC-MRI in rectal cancer: Low primary tumor Ktrans and DeltaR2* peak are significantly associated with lymph node metastasis. J Magn Reson Imaging. 2017 Jul;46(1):194-206. doi: 10.1002/jmri.25566. Epub 2016 Dec 21.
PubMed 28001320
Joranger P, Nesbakken A, Hoff G, Sorbye H, Oshaug A, Aas E. Modeling and validating the cost and clinical pathway of colorectal cancer. Med Decis Making. 2015 Feb;35(2):255-65. doi: 10.1177/0272989X14544749. Epub 2014 Jul 29.
PubMed 25073464
Kalanxhi E, Hektoen HH, Meltzer S, Dueland S, Flatmark K, Ree AH. Circulating proteins in response to combined-modality therapy in rectal cancer identified by antibody array screening. BMC Cancer. 2016 Jul 26;16:536. doi: 10.1186/s12885-016-2601-x.
PubMed 27461255
Meltzer S, Kalanxhi E, Hektoen HH, Dueland S, Flatmark K, Redalen KR, Ree AH. Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer. Oncotarget. 2016 Jun 7;7(23):34907-17. doi: 10.18632/oncotarget.8995.
PubMed 27145458
Ostrup O, Dagenborg VJ, Rodland EA, Skarpeteig V, Silwal-Pandit L, Grzyb K, Berstad AE, Fretland AA, Maelandsmo GM, Borresen-Dale AL, Ree AH, Edwin B, Nygaard V, Flatmark K. Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases. Oncotarget. 2017 Jul 18;8(44):76290-76304. doi: 10.18632/oncotarget.19350. eCollection 2017 Sep 29.
PubMed 29100312
Ree AH, Flatmark K, Saelen MG, Folkvord S, Dueland S, Geisler J, Redalen KR. Tumor phosphatidylinositol 3-kinase signaling in therapy resistance and metastatic dissemination of rectal cancer: opportunities for signaling-adapted therapies. Crit Rev Oncol Hematol. 2015 Jul;95(1):114-24. doi: 10.1016/j.critrevonc.2015.01.003. Epub 2015 Jan 12.
PubMed 25624177
Ree AH, Russnes HG, Heinrich D, Dueland S, Boye K, Nygaard V, Silwal-Pandit L, Ostrup O, Hovig E, Nygaard V, Rodland EA, Nakken S, Oien JT, Johansen C, Bergheim IR, Skarpeteig V, Sathermugathevan M, Sauer T, Lund-Iversen M, Beiske K, Nasser S, Julsrud L, Reisse CH, Ruud EA, Florenes VA, Hagene KT, Aas E, Luras H, Johnsen-Soriano S, Geitvik GA, Lingjaerde OC, Borresen-Dale AL, Maelandsmo GM, Flatmark K. Implementing precision cancer medicine in the public health services of Norway: the diagnostic infrastructure and a cost estimate. ESMO Open. 2017 May 2;2(2):e000158. doi: 10.1136/esmoopen-2017-000158. eCollection 2017.
PubMed 28761742
Spindler KG, Boysen AK, Pallisgard N, Johansen JS, Tabernero J, Sorensen MM, Jensen BV, Hansen TF, Sefrioui D, Andersen RF, Brandslund I, Jakobsen A. Cell-Free DNA in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. Oncologist. 2017 Sep;22(9):1049-1055. doi: 10.1634/theoncologist.2016-0178. Epub 2017 Aug 4.
PubMed 28778958
Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012 May 20;30(15):1755-62. doi: 10.1200/JCO.2011.38.0915. Epub 2012 Apr 2.
PubMed 22473155
Ree AH, Hoye E, Esbensen Y, Beitnes AR, Negard A, Bernklev L, Tetlie LK, Fretland AA, Hamre HM, Kersten C, Hofsli E, Guren MG, Sorbye H, Nilsen HL, Flatmark K, Meltzer S. Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade. Oncoimmunology. 2024 Jun 28;13(1):2372886. doi: 10.1080/2162402X.2024.2372886. eCollection 2024.
PubMed 38952672
Ree AH, Saltyte Benth J, Hamre HM, Kersten C, Hofsli E, Guren MG, Sorbye H, Johansen C, Negard A, Bjornetro T, Nilsen HL, Berg JP, Flatmark K, Meltzer S. First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer-the randomised METIMMOX trial. Br J Cancer. 2024 Jun;130(12):1921-1928. doi: 10.1038/s41416-024-02696-6. Epub 2024 Apr 25.
PubMed 38664577
Meltzer S, Negard A, Bakke KM, Hamre HM, Kersten C, Hofsli E, Guren MG, Sorbye H, Flatmark K, Ree AH. Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer. Br J Cancer. 2022 Dec;127(12):2227-2233. doi: 10.1038/s41416-022-02004-0. Epub 2022 Oct 13.
PubMed 36229579

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 13 Feb 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: METIMMOX: Colorectal Cancer METastasis - Shaping Anti-tumor IMMunity by OXaliplatin
ClinicalTrials.gov ID: NCT03388190
Acronym / sponsor ID: METIMMOX / CA209-9M8
Conditions: Colorectal Cancer Metastatic
Keywords: Colorectal, Cancer, Neoplasm, Nivolumab, Fluorouracil, Metastatic, Oxaliplatin, Leucovorin
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 80 participants (actual)
Lead sponsor: University Hospital, AkershusUniversity, hospital or other
Collaborators: Trondheim University Hospital, Haukeland University Hospital, Hospital of Southern Norway Trust, Oslo University Hospital
Study start: 29 May 2018 (actual)
Primary completion: 18 Mar 2024 (actual)
Study completion: 18 Mar 2024 (actual)
First posted: 2 Jan 2018 (actual)
Results: Posted 13 Feb 2026

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2
Model description: The METIMMOX study is a multicenter open-label randomized phase 2 trial in first-line treatment of MSS/pMMR-mCRC using the standard-of-care Nordic FLOX regimen (control arm) or sequential therapy with the Nordic FLOX regimen and nivolumab (experimental arm), to investigate whether the experimental arm shows superiority in PFS, safety, tolerability, and QoL.

Arm	Type	Receives
Control Arm	Active comparator	Drug: FLOXThe control arm will consist of intermittent treatment with the Nordic FLOX regimen in terms of 8 cycles before break until disease progression, when therapy is reintroduced and administered for another 8 cycles before a new break. This schedule will be continued until progressive disease on ongoing therapy (PFS), intolerable toxicity, withdrawal of consent, or death, whichever occurs first.
Experimental Arm	Experimental	Drug: NivolumabThe experimental arm will consist of repeat 2 cycles of the Nordic FLOX regimen followed by 2 cycles of nivolumab for a total of 8 individual cycles before break until disease progression, when therapy is reintroduced and administered for another total of 8 individual cycles before a new break. This schedule will be continued until progressive disease on ongoing therapy (PFS), intolerable toxicity, withdrawal of consent, or death, whichever occurs first.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (21 listed)

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.

Key exclusion criteria (30 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
NivolumabAlso: Oxaliplatin, 5-fluorouracil, LeucovorinFLOX: Intravenous oxaliplatin 85 mg/m2 on day 1; bolus 5-fluorouracil 500 mg/m2 and bolus Leucovorin on days 1 and 2; IV administration every 2 weeks. Nivolumab: 240 mg flat dose; IV administration every 2 weeks.	Drug	Experimental Arm
FLOXAlso: Oxaliplatin, 5-fluorouracil, LeucovorinFLOX: Intravenous oxaliplatin 85 mg/m2 on day 1; bolus 5-fluorouracil 500 mg/m2 and bolus Leucovorin on days 1 and 2; IV administration every 2 weeks.	Drug	Control Arm

Primary outcome

Primary - Progression-free Survival (PFS)
Time frame: Through study completion (up to 37 months)
To determine PFS, in terms of failure of treatment strategy, on sequential treatment with the Nordic FLOX regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen in previously untreated MSS mCRC. *PFS: radiologic assessment every 8 weeks (following 4 cycles of FLOX or the alternative 2 cycles each of FLOX and nivolumab), according to the Response Evaluation Criteria in Solid Tumors (RECIST) and the RECIST consensus guideline for assessment of response to immune-modulating therapies (iRECIST), wherein complete response = disappearance of the lesion, partial response = at least a 30% decrease in the sum of diameters of target lesions, progressive disease = at least 20% increase in the sum of diameters of target lesions, and stable disease = no shrinkage or increase in size (per Watanabe H, Okada M, Kaji Y, et al. Gan To Kagaku Ryoho. 2009;36(13):2495-2501).

8 secondary outcomes

Secondary 1 - Incidence (Safety) and Grading (Tolerability) of Treatment-related Adverse Events
Time frame: Through study completion (up to 37 months)
Secondary 2 - Objective Response Rate (ORR)
Time frame: Through study completion (up to 37 months)
Secondary 3 - Duration of Response (DOR)
Time frame: Through study completion (up to 37 months)
Secondary 4 - Secondary Curative Resection Rate (SSCRR)
Time frame: Through study completion (up to 37 months)
Secondary 5 - Overall Survival (OS)
Time frame: Through study completion (up to 37 months)
Secondary 6 - Quality-of-life (QoL)
Time frame: Through study completion (up to 37 months)
Secondary 7 - Quality-of-life (QoL)
Time frame: Through study completion (up to 37 months)
Secondary 8 - Quality-of-life (QoL)
Time frame: Through study completion (up to 37 months)

Results and safety

Results posted to the registry on 13 Feb 2026, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Control Arm	38	38
Experimental Arm	38	38

Primary outcome: Primary - Progression-free Survival (PFS)

Time frame: Through study completion (up to 37 months). Median (95% Confidence Interval). Unit: Months of progression-free survival

Measure	Control Arm n = 38	Experimental Arm n = 38
Value	9.2 (6.3 to 12.7)	9.2 (4.5 to 15.0)

8 secondary outcomes are reported in the full results.

Adverse events

Time frame: All patients were monitored for any adverse events throughout the trial and for 1 year after study completion (up to 37 months).. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Control Arm	35 of 38 (92.1%)	0 of 38 (0%)	33 of 38
Experimental Arm	32 of 38 (84.2%)	2 of 38 (5.3%)	34 of 38

Limitations and caveats (from the sponsor): COVID affected the collection of samples and testing regimen due to lack of available staff, distancing regulations, etc.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 13 Feb 2026.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 26888115Dueland S, Ree AH, Groholt KK, Saelen MG, Folkvord S, Hole KH, Seierstad T, Larsen SG, Giercksky KE, Wiig JN, Boye K, Flatmark K. Oxaliplatin-containing Preoperative Therapy in Locally Advanced Rectal Cancer: Local Response, Toxicity and Long-term Outcome. Clin Oncol (R Coll Radiol). 2016 Aug;28(8):532-9. doi: 10.1016/j.clon.2016.01.014. Epub 2016 Feb 14.
Background: PubMed 26968754Flatmark K, Saelen MG, Hole KH, Abrahamsen TW, Fleten KG, Hektoen HH, Redalen KR, Seierstad T, Dueland S, Ree AH. Individual tumor volume responses to short-course oxaliplatin-containing induction chemotherapy in locally advanced rectal cancer - Targeting the tumor for radiation sensitivity? Radiother Oncol. 2016 Jun;119(3):505-11. doi: 10.1016/j.radonc.2016.02.020. Epub 2016 Mar 8.
Background: PubMed 28001320Grovik E, Redalen KR, Storas TH, Negard A, Holmedal SH, Ree AH, Meltzer S, Bjornerud A, Gjesdal KI. Dynamic multi-echo DCE- and DSC-MRI in rectal cancer: Low primary tumor Ktrans and DeltaR2* peak are significantly associated with lymph node metastasis. J Magn Reson Imaging. 2017 Jul;46(1):194-206. doi: 10.1002/jmri.25566. Epub 2016 Dec 21.
Background: PubMed 25073464Joranger P, Nesbakken A, Hoff G, Sorbye H, Oshaug A, Aas E. Modeling and validating the cost and clinical pathway of colorectal cancer. Med Decis Making. 2015 Feb;35(2):255-65. doi: 10.1177/0272989X14544749. Epub 2014 Jul 29.
Background: PubMed 27461255Kalanxhi E, Hektoen HH, Meltzer S, Dueland S, Flatmark K, Ree AH. Circulating proteins in response to combined-modality therapy in rectal cancer identified by antibody array screening. BMC Cancer. 2016 Jul 26;16:536. doi: 10.1186/s12885-016-2601-x.
Background: PubMed 27145458Meltzer S, Kalanxhi E, Hektoen HH, Dueland S, Flatmark K, Redalen KR, Ree AH. Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer. Oncotarget. 2016 Jun 7;7(23):34907-17. doi: 10.18632/oncotarget.8995.
Background: PubMed 29100312Ostrup O, Dagenborg VJ, Rodland EA, Skarpeteig V, Silwal-Pandit L, Grzyb K, Berstad AE, Fretland AA, Maelandsmo GM, Borresen-Dale AL, Ree AH, Edwin B, Nygaard V, Flatmark K. Molecular signatures reflecting microenvironmental metabolism and chemotherapy-induced immunogenic cell death in colorectal liver metastases. Oncotarget. 2017 Jul 18;8(44):76290-76304. doi: 10.18632/oncotarget.19350. eCollection 2017 Sep 29.
Background: PubMed 25624177Ree AH, Flatmark K, Saelen MG, Folkvord S, Dueland S, Geisler J, Redalen KR. Tumor phosphatidylinositol 3-kinase signaling in therapy resistance and metastatic dissemination of rectal cancer: opportunities for signaling-adapted therapies. Crit Rev Oncol Hematol. 2015 Jul;95(1):114-24. doi: 10.1016/j.critrevonc.2015.01.003. Epub 2015 Jan 12.
Background: PubMed 28761742Ree AH, Russnes HG, Heinrich D, Dueland S, Boye K, Nygaard V, Silwal-Pandit L, Ostrup O, Hovig E, Nygaard V, Rodland EA, Nakken S, Oien JT, Johansen C, Bergheim IR, Skarpeteig V, Sathermugathevan M, Sauer T, Lund-Iversen M, Beiske K, Nasser S, Julsrud L, Reisse CH, Ruud EA, Florenes VA, Hagene KT, Aas E, Luras H, Johnsen-Soriano S, Geitvik GA, Lingjaerde OC, Borresen-Dale AL, Maelandsmo GM, Flatmark K. Implementing precision cancer medicine in the public health services of Norway: the diagnostic infrastructure and a cost estimate. ESMO Open. 2017 May 2;2(2):e000158. doi: 10.1136/esmoopen-2017-000158. eCollection 2017.
Background: PubMed 28778958Spindler KG, Boysen AK, Pallisgard N, Johansen JS, Tabernero J, Sorensen MM, Jensen BV, Hansen TF, Sefrioui D, Andersen RF, Brandslund I, Jakobsen A. Cell-Free DNA in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. Oncologist. 2017 Sep;22(9):1049-1055. doi: 10.1634/theoncologist.2016-0178. Epub 2017 Aug 4.
Background: PubMed 22473155Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol. 2012 May 20;30(15):1755-62. doi: 10.1200/JCO.2011.38.0915. Epub 2012 Apr 2.
Derived from this study: PubMed 38952672Ree AH, Hoye E, Esbensen Y, Beitnes AR, Negard A, Bernklev L, Tetlie LK, Fretland AA, Hamre HM, Kersten C, Hofsli E, Guren MG, Sorbye H, Nilsen HL, Flatmark K, Meltzer S. Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade. Oncoimmunology. 2024 Jun 28;13(1):2372886. doi: 10.1080/2162402X.2024.2372886. eCollection 2024.
Individual participant dataSharing planned: No. No plan to share unrandomised, individual participant data with any researchers not involved in the study at the outset.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Anne H Ree, MD PhD principal investigator

University Hospital, Akershus

5 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab and FLOX in people with Colorectal Cancer Metastatic, run by University Hospital, Akershus at 5 sites in Norway.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Feb 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Primary - Progression-free Survival (PFS) (time frame: Through study completion (up to 37 months)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03388190, which also lists 14 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2026; AzTrials last refreshed its copy on 8 Nov 2026.