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    Summary
    EudraCT Number:2020-004366-19
    Sponsor's Protocol Code Number:NIPISAFE_G-106
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-10-16
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-004366-19
    A.3Full title of the trial
    Identification of the optimal combination dosing schedule of nivolumab and ipilimumab in patients with dMMR and/or MSI metastatic colorectal cancer: A GERCOR open-label, randomized, non-comparative, two-stage phase II trial (NIPISAFE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Optimal combination dosing schedule of nivolumab and ipilimumab in patients with dMMR and/or MSI metastatic colorectal cancer
    A.4.1Sponsor's protocol code numberNIPISAFE_G-106
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGERCOR
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBristol Myers Squibb
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGERCOR
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address151 rue du faubourg Saint Antoine
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75011
    B.5.3.4CountryFrance
    B.5.4Telephone number33140298500
    B.5.5Fax number33140298508
    B.5.6E-mailregulatory.affairs@gercor.com.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Opdivo (100 mg/10 ml)
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNIVOLUMAB
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Yervoy (200mg/40ml)
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameIPILIMUMAB
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIPILIMUMAB
    D.3.9.1CAS number 477202-00-9
    D.3.9.3Other descriptive nameIPILIMUMAB
    D.3.9.4EV Substance CodeSUB29397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    dMMR and/or MSI metastatic colorectal cancer
    E.1.1.1Medical condition in easily understood language
    metastatic colorectal cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10052360
    E.1.2Term Colorectal adenocarcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To assess the safety (grade 3 or 4 AEs) profile according to NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 of two different combination schemes of nivolumab plus ipilimumab during the first 24 weeks of treatment,
    - To assess PFS at week 24 for two combination schemes.
    E.2.2Secondary objectives of the trial
    - To assess the safety (AEs, treatment-related AEs and immune-related AEs [iAEs]) and tolerability of two combination schemes,
    - To assess ORR of two combination schemes at weeks 24 and 48, and at 2 years (RECIST v1.1),
    - To assess PFS of two combination schemes at week 48 and at 2 years (RECIST v1.1),
    - To assess PFS of two combination schemes at weeks 24 and 48, and at 2 years (iRECIST),
    - To assess OS of two combination schemes at week 48 and at 2 years (RECIST v1.1),
    - To evaluate the percentage of patients who received immune modulating concomitant medication (e.g., corticosteroids, infliximab, mycophenolate mofetil),
    - To evaluate the percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities,
    - To assess median time to onset and median time to resolution (grade 3-4) of serious AEs (SAEs) and TRAEs,
    - To evaluate changes in HRQoL and patient-reported outcomes (EORTC QLQ-C30 and PRO-CTCAE).

    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    - To explore potential biomarkers associated with the clinical efficacy under two combination schemes,
    - To explore potential biomarkers associated with resistance to immunotherapy,
    - To evaluate the correlation between the toxicity/efficacy and PK parameters,
    - To evaluate the correlation between the toxicity/efficacy and the presence of sarcopenia,
    - To identify predictive biomarkers of resistance to nivolumab and ipilimumab,
    - To identify differential changes in the tumor microenvironment,
    - To identify differential changes in tumor cells.
    E.3Principal inclusion criteria
    1. Signed and dated patient informed consent form and willingness to comply with all study procedures and availability for the study duration,
    2. Age ≥ 18 years,
    3. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2,
    4. Histologically or cytologically confirmed colorectal adenocarcinoma,
    5. Documented advanced or metastatic disease not suitable for complete surgical resection,
    6. At least one measurable lesion as assessed by CT-scan or magnetic resonance imaging (MRI) according to RECIST v1.1 and feasibility of repeated radiological assessments. Participants with lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll provided the lesion(s) have demonstrated clear progression and can be measured accurately,
    7. dMMR and/or MSI tumor status defined by:
    - Loss of MMR protein expression using immunohistochemistry with two (anti-MLH1 and anti-MSH2 or anti-MSH6, and anti-PMS2) or four (anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2) antibodies,
    - and/or ≥ two instable markers by pentaplex polymerase chain reaction (BAT-25, BAT-26, NR-21, NR-24, and NR-27),
    NB: Agreement of the Sponsor (GERCOR) is mandatory to include the patient (the patient’s file will be verified to confirm MSI/dMMR status before inclusion [an anonymized fax] and confirmation of a patient’s allocation will be sent by mail to the Investigator within 24h),
    8. No or one prior line of systemic treatment for metastatic disease:
    - No prior systemic treatment; if patient received neoadjuvant/adjuvant therapy this therapy should be completed > 6 months prior the diagnosis of metastatic or recurrent disease is made,
    - Maximum one prior line of systemic treatment; if patient received one prior line of systemic therapy in the metastatic setting and experienced progression or patient received neoadjuvant/adjuvant therapy and experienced recurrence within ≤ 6 months after completion of therapy,
    9. Availability of a representative tumor specimen for exploratory translational research; tumor tissue specimens, either formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue sections (minimum of 30 positively charged slides) from primary or metastatic site must be submitted to the central laboratory,
    10. Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
    - Hematological status:
    o White blood cell > 2000/µL;
    o Neutrophils > 1500/µL;
    o Platelets > 100.000/µL;
    o Hemoglobin > 9.0 g/dL;
    - Adequate renal function:
    o Serum creatinine level < 150 µM;
    - Adequate liver function:
    o Serum bilirubin ≤ 1.5 x upper normal limit (ULN);
    o Alkaline phosphatase (ALP) ≤ 3 x ULN;
    o Alanine aminotransferase (ALT) ≤ 3.0 x ULN ;
    o Aspartame aminotransferase (AST) ≤ 3.0 x ULN;
    o Prothrombin time (PT)/International normalized ratio (INR) and partial PT (PTT) ≤ 1.5 x ULN unless participants are receiving anticoagulant therapy and their INR is stable and within the recommended range for the desired level of anticoagulation,
    11. Females of childbearing potential must have negative serum pregnancy test within 7 days before starting study treatment,
    12. Women of childbearing potential should use effective contraception during treatment and 5 months thereafter. Males should use condoms during treatment and 7 months thereafter,
    13. Registration in a national health care system (Protection Universelle Maladie [PUMa] included).
    E.4Principal exclusion criteria
    1. Known brain metastases or leptomeningeal metastases,
    2. Persistence of toxicities related to prior chemotherapies grade > 1 (NCI CTCAE v5.0; except alopecia, fatigue, or peripheral sensory neuropathy, which can be grade 2),
    3. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, radiotherapy, immunotherapy),
    4. Major surgical procedure within 4 weeks prior to initiation of study treatment,
    5. Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory antitumor agents,
    6. Patients receiving any investigational drug, biological, immunological therapy within the previous 28 days before study treatment,
    7. Impossibility of submitting to the medical follow-up of the study for geographical, social or psychic reasons,
    8. Patients with an active, known or suspected autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to be enrolled,
    9. History of interstitial lung disease or pneumonitis,
    10. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease,
    11. Prior malignancy active within the previous 3 years, except for:
    - Locally curable cancers that have been apparently cured (e.g. squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast);
    - Lynch syndrome-related non-colorectal cancer in complete remission for > 1 year;
    12. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) virus (HBV) or hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection. Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen antibody test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction testing is negative for HCV ribonucleic acid.
    13. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
    14. Any serious or uncontrolled medical disorder that, in the opinion of Investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results,
    15. Known allergy/hypersensitivity to any component of study agents,
    16. Administration of a (attenuated) live vaccine within 28 days of planned start of study therapy of known need for this vaccine during treatment,
    17. Patient on tutelage or guardianship
    E.5 End points
    E.5.1Primary end point(s)
    - Grade 3 or 4 AEs during the first 24 weeks (NCI CTCAE v5.0),
    - PFS at week 24 (RECIST v1.1).
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    E.5.2Secondary end point(s)
    - AEs (NCI CTCAE v5.0),
    - Treatment-related AEs and iAEs,
    - ORR
    - PFS
    - PFS and ORR
    - OS
    - Percentage of patients who received immune modulating concomitant medication (e.g., corticosteroids, infliximab, mycophenolate mofetil),
    - Percentage of patients who received hormonal replacement therapy for immune-related endocrine toxicities,
    - Median time to onset, median time to resolution (grade 3-4) of SAEs and TRAEs,
    - HRQoL (EORTC QLQ-C30 and NCI-PRO-CTCAE).
    E.5.2.1Timepoint(s) of evaluation of this end point
    - AEs : at every visit during treatment and at 100 days after treatment ends(NCI-CTCAE version 5.0)
    - ORR: 24 weeks; 48 weeks and 2 years(RECIST v1.1)
    - PFS: 24 weeks; 48 weeks and 2 years(RECIST v1.1)
    - OS: weeks 24 and 48, and at 2 years (RECIST v1.1),
    - until 108 weeks of the last patient randomized
    - until 28 days after the last dose
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    ancillary studies (tumor/biopsy and PBMC)
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned20
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 70
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 26
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state96
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 96
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At investigator's discretion
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-09
    P. End of Trial
    P.End of Trial StatusOngoing
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