Hypothesis: Patients with metastatic colorectal cancer with DNA mismatch repair-proficient (pMMR) function / microsatellite-stable (MSS) phenotype harbor a non-immunogenic disease that can be transformed into an immunogenic condition by short-course oxaliplatin-based therapy, and may achieve durable disease control or even tumor eradication by the addition of immune checkpoint blockade therapy to the standard-of-care oxaliplatin-based treatment.
The study has a start-up single-arm design consisting of 2 cycles of the Nordic FLOX regimen followed by 2 cycles of nivolumab for a total of 4 individual cycles (8 weeks, or longer if cycles have been delayed) before radiologic response assessment and patient stratification to continued therapy. Patients who present less than 10% target lesion reduction at the first radiologic response assessment will proceed to standard-of-care treatment at the Clinical Investigator's discretion. Patients will be followed for PFS (from the date of study enrolment). Patients who present 10% or higher target lesion reduction at the first radiologic response assessment will continue treatment with alternating 2 cycles of the Nordic FLOX regimen and 2 cycles of nivolumab. From the time of stratification, radiologic response assessment will be every 8 weeks. After a total of 12 individual cycles (4 initial cycles followed by 8 continuation cycles; Sequence 1), patients will enter a break that will persist until disease progression, following radiologic assessment every 8 weeks during the break, when therapy is reintroduced and administered for another total of 12 individual cycles (Sequence 2) before a new break. This go-and-stop schedule will be continued until progressive disease on ongoing therapy (defining PFS), intolerable toxicity, withdrawal of consent, or death, whichever occurs first.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
80
Q2W Nivolumab: 240 mg fixed dose over 30 minutes, IV administration every 2 weeks
FLOX, Q2W
Akershus University Hospital
Lørenskog, Akershus, Norway
Oslo University Hospital
Oslo, Akershus, Norway
St Olavs Hospital
Trondheim, Trøndelag, Norway
Progression-free survival
To determine PFS, in terms of continuation of treatment strategy, of repeat sequential treatment with the Nordic FLOX regimen and nivolumab in patients with previously untreated unresectable metastatic pMMR/MSS colorectal cancer reaching 10% or higher target lesion reduction at the first radiologic restaging.
Time frame: From date of the first FLOX cycle until the date of disease progression on ongoing therapy or death, whichever occurs first, assessed up to 60 months
Incidence of adverse events
Safety
Time frame: From date of the first FLOX cycle until 100 days following discontinuation of the study treatment, assessed up to 60 months
Grading of adverse events
Tolerability
Time frame: From date of the first FLOX cycle until 100 days following discontinuation of the study treatment, assessed up to 60 months
Objective response rate
ORR
Time frame: Through study completion, an average of 18 months
Duration of response
DoR
Time frame: From date of the best overall response until the date of disease progression, assessed up to 60 months
Secondary surgical curative-intent resection rate
SSCiR
Time frame: Through study completion, an average of 18 months
Overall survival
OS
Time frame: From date of the first FLOX cycle until the date of death, assessed up to 60 months
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