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

NCT03388190 | Completed Phase 2 Results DMC

• 2 other identifiers: CA209-9M82017-001845-29
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 5

Brief 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).

Conditions

Colorectal Cancer Metastatic

Keywords

Colorectal; Cancer; Neoplasm; Nivolumab; Fluorouracil; Metastatic; Oxaliplatin; Leucovorin

Outcome Measures

Primary Outcomes (1)

• 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).

  Through study completion (up to 37 months)

Secondary Outcomes (8)

• Secondary 1 - Incidence (Safety) and Grading (Tolerability) of Treatment-related Adverse Events

  Through study completion (up to 37 months)

• Secondary 2 - Objective Response Rate (ORR)

  Through study completion (up to 37 months)

• Secondary 3 - Duration of Response (DOR)

  Through study completion (up to 37 months)

• Secondary 4 - Secondary Curative Resection Rate (SSCRR)

  Through study completion (up to 37 months)

• Secondary 5 - Overall Survival (OS)

  Through study completion (up to 37 months)

Other Outcomes (6)

• Tertiary - Cost Estimate

  Through study completion (up to 37 months)

• Exploratory 1 - Circulating Biomarkers of Cytotoxic T Lymphocyte Activity

  Through study completion (up to 37 months)

• Exploratory 2 - Circulating Biomarkers of Tumor Response

  Through study completion (maximum of 37 months)

Study Arms (2)

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.

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.

Drug: Nivolumab

Interventions

Nivolumab DRUG

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.

Also known as: Oxaliplatin, 5-fluorouracil, Leucovorin

Experimental Arm

FLOX DRUG

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.

Also known as: Oxaliplatin, 5-fluorouracil, Leucovorin

Control Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Hospital, Akershus: lead
• Trondheim University Hospital: collaborator
• Haukeland University Hospital: collaborator
• Hospital of Southern Norway Trust: collaborator
• Oslo University Hospital: collaborator

Study Sites (5)

Haukeland University Hospital

Bergen, 5021, Norway

Location

Hospital of Southern Norway, Department of Oncology

Kristiansand, 4604, Norway

Location

Oslo University Hospital

Oslo, 0424, Norway

Location

Akershus University Hospital

Oslo, 1478, Norway

Location

St Olav's Hospital - Trondheim University Hospital

Trondheim, 7006, Norway

Location

Related Publications (13)

• 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.

  PMID: 26888115 BACKGROUND

• 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.

  PMID: 26968754 BACKGROUND

• 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.

  PMID: 28001320 BACKGROUND

• 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.

  PMID: 25073464 BACKGROUND

• 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.

  PMID: 27461255 BACKGROUND

• 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.

  PMID: 27145458 BACKGROUND

• 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.

  PMID: 29100312 BACKGROUND

• 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.

  PMID: 25624177 BACKGROUND

• 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.

  PMID: 28761742 BACKGROUND

• 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.

  PMID: 28778958 BACKGROUND

• 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.

  PMID: 22473155 BACKGROUND

• 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.

  PMID: 38664577 DERIVED

• 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.

  PMID: 36229579 DERIVED

MeSH Terms

Conditions

Neoplasms; Neoplasm Metastasis

Interventions

Nivolumab; Oxaliplatin; Fluorouracil; Leucovorin

Condition Hierarchy (Ancestors)

Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Coordination Complexes; Organic Chemicals; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes

Limitations and Caveats

COVID affected the collection of samples and testing regimen due to lack of available staff, distancing regulations, etc.

Results Point of Contact

• Title: Anne Hansen Ree
• Organization: Akershus University Hospital

a.h.ree@medisin.uio.no

(+47) 48257968

Study Officials

• Anne H Ree, MD PhD

  University Hospital, Akershus

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, MD PhD

Model Details: 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.

Study Record Dates

• First Submitted: December 8, 2017
• First Posted: January 2, 2018
• Study Start: May 29, 2018
• Primary Completion: March 18, 2024
• Study Completion: March 18, 2024
• Last Updated: February 13, 2026
• Results First Posted: February 13, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

NO (5)