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| ID | Type | Description | Link |
|---|---|---|---|
| 2017-001845-29 | EudraCT Number |
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| Name | Class |
|---|---|
| Trondheim University Hospital | OTHER |
| Haukeland University Hospital | OTHER |
| Hospital of Southern Norway Trust | OTHER |
| Oslo University Hospital |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Secondary 1 - Incidence (Safety) and Grading (Tolerability) of Treatment-related Adverse Events | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Tertiary - Cost Estimate | 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. | Through study completion (up to 37 months) |
| Exploratory 1 - Circulating Biomarkers of Cytotoxic T Lymphocyte Activity |
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:
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:
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:
Patient has undergone treatment with any IMP that may interfere with the study treatment within 4 weeks prior to first administration of study drug.
Patient has known hypersensitivity to any of the study IMP components.
Patient has ECOG performance status 2 or worse.
Patient has serum/plasma CRP of 60 mg/L or higher.
Patient does not meet the following requirements at baseline: adequate bone marrow function without current use of colony-stimulating factors (minimum values of neutrophils 1.5 x109/L, platelets 100 x109/L, hemoglobin 10 g/dL), adequate liver function (maximum values of AST/ALT 5x ULN and bilirubin 2x ULN; albumin value of 30 g/L or higher; INR within normal level), adequate renal function (maximum creatinine value of 1.5x ULN).
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 ( clinically visible lesion confined to cervix uteri), 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.
Patient has significant cardiac, pulmonary, or other medical illness that would limit activity of daily life or survival.
Patient is pregnant or breastfeeding.
Patient has any other reason, in the opinion of Clinical Investigator, not to participate in the study.
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| Name | Affiliation | Role |
|---|---|---|
| Anne H Ree, MD PhD | University Hospital, Akershus | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Haukeland University Hospital | Bergen | 5021 | Norway | |||
| Hospital of Southern Norway, Department of Oncology |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26888115 | Background | 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. | |
| 26968754 |
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No plan to share unrandomised, individual participant data with any researchers not involved in the study at the outset.
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| ID | Title | Description |
|---|---|---|
| FG000 | Control Arm | The control arm consisted of intermittent treatment with the Nordic FLOX regimen in terms of 8 cycles before break until disease progression, when therapy was reintroduced and administered for another 8 cycles before a new break. This schedule was continued until progressive disease on ongoing therapy (PFS), intolerable toxicity, withdrawal of consent, or death, whichever occured first. FLOX: 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. |
| FG001 | Experimental Arm | The experimental arm consisted 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 was reintroduced and administered for another total of 8 individual cycles before a new break. This schedule was continued until progressive disease on ongoing therapy (PFS), intolerable toxicity, withdrawal of consent, or death, whichever occurs first. Nivolumab: 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Control Arm | 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. FLOX: 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | Posted | Median | 95% Confidence Interval | Months of progression-free survival | Through study completion (up to 37 months) |
|
All patients were monitored for any adverse events throughout the trial and for 1 year after study completion (up to 37 months).
Definitions do not differ from the clinicaltrials.gov definition.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Control Arm | The control arm consisted of intermittent treatment with the Nordic FLOX regimen in terms of 8 cycles before break until disease progression, when therapy was reintroduced and administered for another 8 cycles before a new break. This schedule was continued until progressive disease on ongoing therapy (PFS), intolerable toxicity, withdrawal of consent, or death, whichever occured first. FLOX: 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Arterial hypertension | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hepatobiliary disorders - Other, Increased hepatic enzymes | Hepatobiliary disorders | CTCAE (4.0) | Systematic Assessment | Grade 2 |
COVID affected the collection of samples and testing regimen due to lack of available staff, distancing regulations, etc.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Anne Hansen Ree | Akershus University Hospital | (+47) 48257968 | a.h.ree@medisin.uio.no |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 2, 2018 | Jul 30, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 6, 2024 | Jul 30, 2024 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D009369 | Neoplasms |
| D009362 | Neoplasm Metastasis |
| ID | Term |
|---|---|
| D009385 | Neoplastic Processes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000077594 | Nivolumab |
| D000077150 | Oxaliplatin |
| D005472 | Fluorouracil |
| D002955 | Leucovorin |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| OTHER |
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.
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|
| 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. |
|
|
| Through study completion (up to 37 months) |
| Secondary 2 - Objective Response Rate (ORR) | 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. | Through study completion (up to 37 months) |
| Secondary 3 - Duration of Response (DOR) | 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. | Through study completion (up to 37 months) |
| Secondary 4 - Secondary Curative Resection Rate (SSCRR) | 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. | Through study completion (up to 37 months) |
| Secondary 5 - Overall Survival (OS) | 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. | Through study completion (up to 37 months) |
| Secondary 6 - Quality-of-life (QoL) | 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] | Through study completion (up to 37 months) |
| Secondary 7 - Quality-of-life (QoL) | 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. | Through study completion (up to 37 months) |
| Secondary 8 - Quality-of-life (QoL) | 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). | Through study completion (up to 37 months) |
To monitor the individual patients' levels of PTEN (phosphatase and tensin homolog) phosphatase activity in peripheral blood mononuclear cells throughout study treatment. |
| Through study completion (up to 37 months) |
| Exploratory 2 - Circulating Biomarkers of Tumor Response | To monitor the individual patients' levels of plasma tumor DNA throughout study treatment. Measure is variant allele frequency (VAF, in %) relative to baseline. | Through study completion (maximum of 37 months) |
| Exploratory 3 - Circulating Biomarkers of Immune Cell Death (ICD) | Measures of circulating immune factors and T cell phenotypes in serial serum/plasma/whole blood samples collected corresponding to each change of therapy in the sequential regimen. | Through study completion (maximum of 37 months) |
| Exploratory 4 - Functional MR (Magnetic Resonance) Imaging Biomarkers | To monitor the individual patients' changes in liver/peritoneal functional MR signals throughout study treatment. The COVID pandemic stopped the collection of data for this trial due to lack of available staff and equipment, as well as analysts. Therefore, no data will be presented for this outcome. | Through study completion (up to 37 months) |
| Exploratory 5 - Histologic and Molecular Tumor Biomarkers | To monitor the individual patients' changes in liver/peritoneal tissue composition throughout study treatment. | Through study completion (month 37) |
| Kristiansand |
| 4604 |
| Norway |
| Oslo University Hospital | Oslo | 0424 | Norway |
| Akershus University Hospital | Oslo | 1478 | Norway |
| St Olav's Hospital - Trondheim University Hospital | Trondheim | 7006 | Norway |
| 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. |
| 28001320 | 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. |
| 25073464 | 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. |
| 27461255 | 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. |
| 27145458 | 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. |
| 29100312 | 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. |
| 25624177 | 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. |
| 28761742 | 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. |
| 28778958 | 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. |
| 22473155 | 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. |
| 38952672 | Derived | Ree AH, Hoye E, Esbensen Y, Beitnes AR, Negard A, Bernklev L, Tetlie LK, Fretland AA, Hamre HM, Kersten C, Hofsli E, Guren MG, Sorbye H, Nilsen HL, Flatmark K, Meltzer S. Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade. Oncoimmunology. 2024 Jun 28;13(1):2372886. doi: 10.1080/2162402X.2024.2372886. eCollection 2024. |
| 38664577 | Derived | 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. |
| 36229579 | 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. |
| BG001 | Experimental Arm | 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. Nivolumab: 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Control Arm |
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. FLOX: 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. |
| OG001 | Experimental Arm | 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. Nivolumab: 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. |
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| Secondary | Secondary 1 - Incidence (Safety) and Grading (Tolerability) of Treatment-related Adverse Events | 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). | Posted | Number | participants showing an adverse event | Through study completion (up to 37 months) |
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| Secondary | Secondary 2 - Objective Response Rate (ORR) | 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. | ORR for experimental arm 17/36 (47%) versus 20/31 (65%) in control arm, p=0.16. | Posted | Count of Participants | Participants | Through study completion (up to 37 months) |
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| Secondary | Secondary 3 - Duration of Response (DOR) | 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. | Posted | Median | 95% Confidence Interval | Months with durable response | Through study completion (up to 37 months) |
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| Secondary | Secondary 4 - Secondary Curative Resection Rate (SSCRR) | 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. | Number of patients who underwent secondary curative resection (surgery to excise metastases) | Posted | Count of Participants | Participants | Through study completion (up to 37 months) |
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| Secondary | Secondary 5 - Overall Survival (OS) | 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. | Posted | Median | 95% Confidence Interval | Months | Through study completion (up to 37 months) |
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| Secondary | Secondary 6 - Quality-of-life (QoL) | 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] | Not Posted | Dec 2025 | Through study completion (up to 37 months) | Participants |
| Secondary | Secondary 7 - Quality-of-life (QoL) | 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. | Not Posted | Dec 2025 | Through study completion (up to 37 months) | Participants |
| Secondary | Secondary 8 - Quality-of-life (QoL) | 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). | Not Posted | Dec 2025 | Through study completion (up to 37 months) | Participants |
| Other Pre-specified | Tertiary - Cost Estimate | 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. | Not Posted | Dec 2025 | Through study completion (up to 37 months) | Participants |
| Other Pre-specified | Exploratory 1 - Circulating Biomarkers of Cytotoxic T Lymphocyte Activity | To monitor the individual patients' levels of PTEN (phosphatase and tensin homolog) phosphatase activity in peripheral blood mononuclear cells throughout study treatment. | Data not collected; Due to the COVID pandemic we could not collect enough samples. | Posted | Through study completion (up to 37 months) |
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| Other Pre-specified | Exploratory 2 - Circulating Biomarkers of Tumor Response | To monitor the individual patients' levels of plasma tumor DNA throughout study treatment. Measure is variant allele frequency (VAF, in %) relative to baseline. | Individuals dropping out either withdrew consent or died from their disease. During treatment patients were seen every two weeks, with blood samples drawn for experimental purposes every other visit; off treatment, they were seen every two months, with blood samples taken at those visits. | Posted | Mean | Full Range | Variant Allele Frequency (VAF, in %) | Through study completion (maximum of 37 months) |
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| Other Pre-specified | Exploratory 3 - Circulating Biomarkers of Immune Cell Death (ICD) | Measures of circulating immune factors and T cell phenotypes in serial serum/plasma/whole blood samples collected corresponding to each change of therapy in the sequential regimen. | Not Posted | Dec 2025 | Through study completion (maximum of 37 months) | Participants |
| Other Pre-specified | Exploratory 4 - Functional MR (Magnetic Resonance) Imaging Biomarkers | To monitor the individual patients' changes in liver/peritoneal functional MR signals throughout study treatment. The COVID pandemic stopped the collection of data for this trial due to lack of available staff and equipment, as well as analysts. Therefore, no data will be presented for this outcome. | Not Posted | Through study completion (up to 37 months) | Participants |
| Other Pre-specified | Exploratory 5 - Histologic and Molecular Tumor Biomarkers | To monitor the individual patients' changes in liver/peritoneal tissue composition throughout study treatment. | Only one participant's samples were analysed due to patients declining to participate. Liver and peritoneal metastatic tumor tissue samples were taken at several timepoints during one experimental patient's treatment. | Posted | Number | Number of T-cell receptor sequences | Through study completion (month 37) |
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| 33 |
| 38 |
| 35 |
| 38 |
| 0 |
| 38 |
| EG001 | Experimental Arm | The experimental arm consisted 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 was reintroduced and administered for another total of 8 individual cycles before a new break. This schedule was continued until progressive disease on ongoing therapy (PFS), intolerable toxicity, withdrawal of consent, or death, whichever occurs first. Nivolumab: 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. | 34 | 38 | 32 | 38 | 2 | 38 |
| Atrial fibrillation | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
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| Cardiac asystole | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
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| Dehydration | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
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| Edema | Cardiac disorders | CTCAE (4.0) | Systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Ileus | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Anemia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Neutropenia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Thrombocytopenia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Venous thromboembolism | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Fever | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Infection | Infections and infestations | CTCAE (4.0) | Systematic Assessment |
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| Hypokalemia | Metabolism and nutrition disorders | CTCAE (4.0) | Systematic Assessment |
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| Fatigue | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Pain | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Paresthesia | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Spinal cord compression | Nervous system disorders | CTCAE (4.0) | Systematic Assessment |
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| Renal failure | Renal and urinary disorders | CTCAE (4.0) | Systematic Assessment |
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| Urinary retention | Renal and urinary disorders | CTCAE (4.0) | Systematic Assessment |
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| Dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Systematic Assessment |
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| Infusion-related reaction | Product Issues | CTCAE (4.0) | Systematic Assessment |
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| Arthritis | Immune system disorders | CTCAE (4.0) | Systematic Assessment |
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| Hyperglycaemia | Immune system disorders | CTCAE (4.0) | Systematic Assessment |
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| Hypophysitis | Immune system disorders | CTCAE (4.0) | Systematic Assessment |
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| Increased hepatic enzymes | Immune system disorders | CTCAE (4.0) | Systematic Assessment |
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| Pneumonitis | Immune system disorders | CTCAE (4.0) | Systematic Assessment |
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| Rash | Immune system disorders | CTCAE (4.0) | Systematic Assessment |
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Not provided
Not provided
Not provided
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005575 | Formyltetrahydrofolates |
| D013763 | Tetrahydrofolates |
| D005492 | Folic Acid |
| D011622 | Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D003067 | Coenzymes |
| D045762 | Enzymes and Coenzymes |
| Patients displaying a Grade 4 Adverse Event |
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| 1 Month after first treatment |
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| 2 months after first treatment |
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| 3 months after first treatment |
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| 4 months after first treatment |
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| 6 months after first treatment |
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| 8 months after first treatment |
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| 10 months after first treatment |
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| 12 months after first treatment |
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| 14 months after first treatment |
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| 16 months after first treatment |
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| 18 months after first treatment |
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| 20 months after first treatment |
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| 22 months after first treatment |
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| 23 months after first treatment |
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| 24 months after first treatment |
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| 25 months after first treatment |
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| 26 months after first treatment |
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| 28 months after first treatment |
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| 29 months after first treatment |
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| 30 months after first treatment |
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