Colorectal Cancer Metastatic
Conditions
Keywords
Colorectal, Cancer, Neoplasm, Nivolumab, Fluorouracil, Metastatic, Oxaliplatin, Leucovorin
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).
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.
Interventions
DRUGNivolumab
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.
DRUGFLOX
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.
Sponsors
University Hospital, Akershus
Trondheim University Hospital
Haukeland University Hospital
Hospital of Southern Norway Trust
Oslo University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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. * 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.
Exclusion criteria
* 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. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary - Progression-free Survival (PFS) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary 1 - Incidence (Safety) and Grading (Tolerability) of Treatment-related Adverse Events | Through study completion (up to 37 months) | 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). |
| Secondary 2 - Objective Response Rate (ORR) | Through study completion (up to 37 months) | 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. |
| Secondary 3 - Duration of Response (DOR) | Through study completion (up to 37 months) | 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. |
| Secondary 4 - Secondary Curative Resection Rate (SSCRR) | Through study completion (up to 37 months) | 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. |
| Secondary 5 - Overall Survival (OS) | Through study completion (up to 37 months) | 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. |
| Secondary 6 - Quality-of-life (QoL) | Through study completion (up to 37 months) | 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). \[Scoring information summarised from the EORTC QLQ-C30 Scoring manual, 3rd edition\] |
| Secondary 7 - Quality-of-life (QoL) | Through study completion (up to 37 months) | 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. |
| Secondary 8 - Quality-of-life (QoL) | Through study completion (up to 37 months) | 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). |
Countries
Norway
Contacts
PRINCIPAL_INVESTIGATORAnne H Ree, MD PhD
University Hospital, Akershus
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 64.5 years |
| Race and Ethnicity Not Collected | 0 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 33 / 38 | 34 / 38 |
| other Total, other adverse events | 0 / 38 | 2 / 38 |
| serious Total, serious adverse events | 35 / 38 | 32 / 38 |
Outcome results
None listed