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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.

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.

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.

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.

FLOX

Anne H Ree, MD PhD

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).

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.

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.

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

No plan to share unrandomised, individual participant data with any researchers not involved in the study at the outset.

To compare costs for the resource use (in diagnostic work-up, treatment, and any adverse events) for the sequential therapy with that of the standard-of-care, applying a model specifically developed for CRC.

To monitor the individual patients' levels of PTEN (phosphatase and tensin homolog) phosphatase activity in peripheral blood mononuclear cells throughout study treatment.

To monitor the individual patients' levels of plasma tumor DNA throughout study treatment.

To monitor the individual patients' levels of serum/plasma immune proteins throughout study treatment.

To monitor the individual patients' changes in liver/peritoneal functional MR signals throughout study treatment.

To monitor the individual patients' changes in liver/peritoneal tissue composition throughout study treatment.

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).

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.

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.

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.

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.

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.

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).

Per the EORTC Scoring manual, the 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). \[Scoring information summarised from the EORTC QLQ-C30 Scoring manual, 3rd edition\]

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.

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 questionbeing 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).

Trondheim University Hospital

Haukeland University Hospital

Hospital of Southern Norway Trust

Oslo University Hospital

University Hospital, Akershus

Professor, MD PhD

Cetuximab

500 mg/m² every second week, intravenous infusion, 8 cycles

Cetuximab (Erbitux)

Given in combination day 1 and 2, every second week, 8 cycles

Oxaliplatin (Eloxatin) + Fluorouracil + folinic acid

Per Pfeiffer, MD

The Nordic FLOX-regime consists of a combination of bolus 5-FU, leukovorin and oxaliplatin (Eloxatin®). Cetuximab (Erbitux®) is an antibody against the epidermal growth factor receptor (EGFR). The combination of FLOX and weekly Erbitux has been investigated in the Nordic VII study where 571 patients were randomized to FLOX (regime A) or FLOX + Erbitux (regime B or C). Effect-data has not yet been published but the combination is well tolerated, and other studies have shown that Erbitux administered with chemotherapy seem to be more efficient than chemotherapy alone.

The main purpose with this study is to investigate the effect of FLOX and Erbitux given every second week as first line treatment for patients with metastatic colorectal cancer and K-RAS wildtype tumor.

The latest accessible data regarding treatment towards EGFR and K-RAS mutations shows that patients with K-RAS wildtype responds better to treatment than patients with K-RAS mutations.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
METIMMOX: Colorectal Cancer METastasis - Shaping Anti-tumor IMMunity by OXaliplatin	NCT03388190	Colorectal Canc...	Nivolumab FLOX	18 Years -	University Hospital, Akershus
FLOX + Cetuximab (Erbitux®) for Patients With Metastatic Colorectal Cancer and Wild Type K-RAS Tumor	NCT00660582	Metastatic Colo...	Cetuximab (Erbi... Oxaliplatin (El...	18 Years - 75 Years	Odense University Hospital
METIMMOX: Colorectal Cancer METastasis - Shaping Anti-tumor IMMunity by OXaliplatin	NCT03388190	Colorectal Canc...	Nivolumab FLOX	18 Years -	University Hospital, Akershus

Spots Global Cancer Trial Database for flox

Every month we try and update this database with for flox cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for flox

Every month we try and update this database with for flox cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for flox cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.