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

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ClinicalTrials.gov Identifier: NCT03388190
Recruitment Status : Recruiting
First Posted : January 2, 2018
Last Update Posted : February 1, 2019
Sponsor:
Collaborators:
Trondheim University Hospital
Haukeland University Hospital
Hospital of Southern Norway Trust
Oslo University Hospital
Information provided by (Responsible Party):
Prof Dr Anne Hansen Ree, University Hospital, Akershus

Tracking Information
First Submitted Date  ICMJE December 8, 2017
First Posted Date  ICMJE January 2, 2018
Last Update Posted Date February 1, 2019
Actual Study Start Date  ICMJE May 29, 2018
Estimated Primary Completion Date November 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 23, 2017)
Primary - progression-free survival (PFS) [ Time Frame: Through study completion, an average of 15 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03388190 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: December 23, 2017)
  • Secondary 1 - Incidence (safety) and grading (tolerability) of treatment-related adverse events [ Time Frame: Through study completion, an average of 15 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.
  • Secondary 2 - Objective response rate (ORR) [ Time Frame: Through study completion, an average of 15 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) [ Time Frame: Through study completion, an average of 15 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) [ Time Frame: Through study completion, an average of 15 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) [ Time Frame: Through study completion, an average of 15 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) [ Time Frame: Through study completion, an average of 15 months ]
    To monitor and compare QoL alterations during therapy courses using the consensus module EORTC QLQ-C30.
  • Secondary 7 - Quality-of-life (QoL) [ Time Frame: Through study completion, an average of 15 months ]
    To monitor and compare QoL alterations during therapy courses using the consensus module EORTC QLQ-CIPN20.
  • Secondary 8 - Quality-of-life (QoL) [ Time Frame: Through study completion, an average of 15 months ]
    To monitor and compare QoL alterations during therapy courses using the consensus module EQ-5D-5L.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: December 23, 2017)
  • Tertiary - Cost estimate [ Time Frame: Through study completion, an average of 15 months ]
    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.
  • Exploratory 1 - Circulating biomarkers of cytotoxic T lymphocyte activity [ Time Frame: Through study completion, an average of 15 months ]
    To monitor the individual patients' levels of PTEN phosphatase activity in peripheral blood mononuclear cells throughout study treatment.
  • Exploratory 2 - Circulating biomarkers of tumor response [ Time Frame: Through study completion, an average of 15 months ]
    To monitor the individual patients' levels of plasma tumor DNA throughout study treatment.
  • Exploratory 3 - Circulating biomarkers of tumor immunogenic cell death (ICD) [ Time Frame: Through study completion, an average of 15 months ]
    To monitor the individual patients' levels of serum/plasma immune proteins throughout study treatment.
  • Exploratory 4 - Functional MR imaging biomarkers [ Time Frame: Through study completion, an average of 15 months ]
    To monitor the individual patients' changes in liver/peritoneal functional MR signals throughout study treatment.
  • Exploratory 5 - Histologic and molecular tumor biomarkers [ Time Frame: Through study completion, an average of 15 months ]
    To monitor the individual patients' changes in liver/peritoneal tissue composition throughout study treatment.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE METIMMOX: Colorectal Cancer METastasis - Shaping Anti-tumor IMMunity by OXaliplatin
Official Title  ICMJE METIMMOX: Colorectal Cancer METastasis - Shaping Anti-tumor IMMunity by OXaliplatin
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) metastatic colorectal cancer (mCRC).
Detailed Description

Hypothesis: Most patients with mCRC harbor tumor that can be transformed into an immunogenic disease by oxaliplatin, 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 regimen and nivolumab compared with the standard-of-care Nordic FLOX regimen in previously untreated MSS 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
The METIMMOX study is a multicenter open-label randomized phase 2 trial in first-line treatment of MSS 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Colorectal Cancer Metastatic
Intervention  ICMJE
  • Drug: 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.

    Other Names:
    • Oxaliplatin
    • 5-fluorouracil
    • Leucovorin
  • Drug: 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.
    Other Names:
    • Oxaliplatin
    • 5-fluorouracil
    • Leucovorin
Study Arms  ICMJE
  • Active Comparator: 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), unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
    Intervention: Drug: FLOX
  • Experimental: 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), unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
    Intervention: Drug: Nivolumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 23, 2017)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 1, 2020
Estimated Primary Completion Date November 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 less than 60 mg/L.
    • 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.
    • 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.
    • Albumin no lower than 30 g/L.
    • INR within normal level.
    • Creatinine no higher than 1.5xULN.
  • 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 exclusion criteria.
  • 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 5xULN and bilirubin 2xULN; albumin value of 30 g/L or higher; INR within normal level), adequate renal function (maximum creatinine value of 1.5xULN).
  • 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.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Anne H Ree, MD PhD +47 67960000 a.h.ree@medisin.uio.no
Contact: Dawn J Patrick-Brown, MSc +47 67960000 d.j.patrick-brown@medisin.uio.no
Listed Location Countries  ICMJE Norway
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03388190
Other Study ID Numbers  ICMJE CA209-9M8
2017-001845-29 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: No plan to share unrandomised, individual participant data with any researchers not involved in the study at the outset.
Responsible Party Prof Dr Anne Hansen Ree, University Hospital, Akershus
Study Sponsor  ICMJE University Hospital, Akershus
Collaborators  ICMJE
  • Trondheim University Hospital
  • Haukeland University Hospital
  • Hospital of Southern Norway Trust
  • Oslo University Hospital
Investigators  ICMJE
Principal Investigator: Anne H Ree, MD PhD University Hospital, Akershus
PRS Account University Hospital, Akershus
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP