METIMMOX-2: Metastatic pMMR/MSS Colorectal Cancer - Shaping Anti-Tumor Immunity by Oxaliplatin
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 2 |
Detailed Description
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 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 Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Experimental Arm 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 before radiologic response assessment and patient stratification to continued therapy or not. 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 who present 10% or higher target lesion reduction at the first radiologic response assessment will continue with alternating 2 cycles of the Nordic FLOX regimen and 2 cycles of nivolumab in a go-and-stop schedule until progressive disease on ongoing therapy (defining PFS), intolerable toxicity, withdrawal of consent, or death, whichever occurs first. |
Drug: Nivolumab
Q2W
Nivolumab: 240 mg fixed dose over 30 minutes, IV administration every 2 weeks
Other Names:
Drug: Oxaliplatin
FLOX, Q2W
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Progression-free survival [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]
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.
Secondary Outcome Measures
- Incidence of adverse events [From date of the first FLOX cycle until 100 days following discontinuation of the study treatment, assessed up to 60 months]
Safety
- Grading of adverse events [From date of the first FLOX cycle until 100 days following discontinuation of the study treatment, assessed up to 60 months]
Tolerability
- Objective response rate [Through study completion, an average of 18 months]
ORR
- Duration of response [From date of the best overall response until the date of disease progression, assessed up to 60 months]
DoR
- Secondary surgical curative-intent resection rate [Through study completion, an average of 18 months]
SSCiR
- Overall survival [From date of the first FLOX cycle until the date of death, assessed up to 60 months]
OS
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patient has histologically verified pMMR/MSS colorectal adenocarcinoma (also comprising the mucinous adenocarcinoma and signet-ring cell carcinoma entities).
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Patient is ambulatory with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
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Patient is at least 18 years of age.
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Patient has radiologically measurable metastatic disease.
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Patient has an infradiaphragmatic metastatic lesion that can be biopsied.
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Patient has not had previous systemic cytotoxic therapy for the metastatic disease, except for previous neoadjuvant treatment.
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Patient is eligible for the Nordic FLOX regimen when it would be the preferred treatment option for first-line therapy in routine practice.
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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:
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Hemoglobin at least 10.0 g/dL
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Neutrophils at least 1.5 x10(9)/L (without current use of colony-stimulating factors).
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Platelets at least 100 x10(9)/L. - C-reactive protein less than 60 mg/L
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AST/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. o Bilirubin no higher than 1.5xULN when patient does not have metastatic disease in the liver or no higher than 2xULN when patient has metastatic disease in the liver
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Albumin no lower than 30 g/L. - INR within normal level
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Creatinine no higher than 1.5xULN
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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
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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
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Woman is not breastfeeding
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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
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Signed informed consent form and expected cooperation of the patients for the treatment and follow-up must be obtained and documented according to International Conference on Harmonization - Good Clinical Practice and national/local regulations
Exclusion Criteria:
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Patient has metastatic dMMR/MSI colorectal cancer.
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Patient has initially resectable metastatic disease for which neoadjuvant therapy is deemed superfluous.
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Patient has supradiaphragmatic metastatic disease as the sole site(s).
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Patient has untreated or symptomatic brain metastasis (patient must be symptom-free without the use of corticosteroids).
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Patient has experienced a period of less than 6 months since discontinuation of neoadjuvant or adjuvant oxaliplatincontaining chemotherapy.
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Patient is ineligible for full (100%) chemotherapy doses at first treatment cycle.
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Patient has partial or complete dihydropyrimidine dehydrogenase (DPD) deficiency.
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Patient has had radiation therapy against the only measurable lesion within 4 weeks of start of study treatment.
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Patient has a medical condition treated with anticoagulant medication that cannot be replaced by low molecular weight heparin or a direct oral anticoagulant during active study treatment.
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Patient has a nervous system disorder worse than CTCAE grade 1.
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Patient has any medical condition that will preclude him/her from immune checkpoint blockade therapy, such as:
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Active or chronic hepatitis B or hepatitis C. - Known history of human immunodeficiency virus or acquired immunodeficiency-related illnesses.
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Diagnosis of immunodeficiency or medical condition requiring systemic steroids or other forms of immunosuppressive therapy.
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Autoimmune disease that has required systemic therapy within the past 2 years.
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Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study therapy.
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Active infection or chronic infection requiring chronic suppressive antibiotics.
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Known history of previous diagnosis of tuberculosis.
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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.
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Patient has any medical condition or needs to use medication, as listed in the SmPC of each Investigational Medical Product (IMP), that will preclude him/her from receiving treatment with IMP, such as:
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Pernicious anemia or anemias due to vitamin B12 deficiency (SmPC-listed contraindications for folinic acid).
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A known complete absence of DPD activity.
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Has been treated with brivudine, sorivudine, or their chemically related analogs, which are potent inhibitors of the enzyme DPD that degrades fluorouracil. Fluorouracil must not be taken within 4 weeks of treatment with brivudine, sorivudine, or their chemically related analogs.
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Other SmPC-listed contraindications for the IMPs are covered by other exclusion criteria.
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Patient has undergone treatment with any IMP that may interfere with the study treatment within 4 weeks prior to first administration of study drug.
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Patient has known hypersensitivity to any of the study IMP components.
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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, 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.
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Patient has significant cardiac, pulmonary, or other medical illness that would limit activity of daily life or survival.
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Patient is pregnant or breastfeeding.
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Patient has any other reason, in the opinion of Clinical Investigator, not to participate in the study.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | St Olavs Hospital | Trondheim | Trondelag | Norway | 7006 |
2 | Akershus University Hospital | Lørenskog | Viken | Norway | 1478 |
3 | Oslo University Hospital | Oslo | Viken | Norway | 0424 |
Sponsors and Collaborators
- University Hospital, Akershus
- Oslo University Hospital
- St. Olavs Hospital
Investigators
- Study Chair: Christian Kersten, MD, PhD, University Hospital, Akershus
Study Documents (Full-Text)
None provided.More Information
Publications
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