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    Summary
    EudraCT Number:2015-003199-56
    Sponsor's Protocol Code Number:CA209-322
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-09-16
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2015-003199-56
    A.3Full title of the trial
    An open-label, single-arm, phase II, multicenter study to evaluate the efficacy of nivolumab/ipilimumab combination therapy in metastatic melanoma patients with symptomatic brain metastases.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the effect of nivolumab and ipilimumab in patients with metastatic melanoma and brain metastases that produces symptoms.
    A.3.2Name or abbreviated title of the trial where available
    Nivo/Ipi combination therapy in symptomatic brain metastases
    A.4.1Sponsor's protocol code numberCA209-322
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02621515
    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 SponsorUniversity Medical Center Groningen
    B.1.3.4CountryNetherlands
    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.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Groningen
    B.5.2Functional name of contact pointDepartment of Medical Oncology
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9713 GZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31503616161
    B.5.5Fax number+31503614862
    B.5.6E-mailg.a.p.hospers@umcg.nl
    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 nivolumab (Opdivo)
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) Yes
    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 ipilimumab (Yervoy)
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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) Yes
    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
    Metastatic (stage IV) melanoma with symptomatic brain metastases
    E.1.1.1Medical condition in easily understood language
    Metastatic melanoma with brain metastases that produces symptoms
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Main objective of this phase 2 trial is to evaluate efficacy of nivolumab and ipilimumab in symptomatic brain metastases of metastatic melanoma patients.
    E.2.2Secondary objectives of the trial
    As secondary objective, the efficacy will be compared between patients with previously locally treated (e.g. surgery, stereotactic radiotherapy) and untreated brain metastases. Furthermore, difference in response between intra- and extra cranial metastases will be evaluated. Secondary efficacy parameters will be assessed in addition, including survival. Safety and tolerability of nivolumab and ipilimumab will be assessed, because this is the first time nivolumab and ipilimumab is administrated to patients with symptomatic brain metastases.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects must sign informed consent prior to inclusion in this trial.
    2. Subjects must be ≥18 years of age and competent to give informed consent.
    3. Histologically confirmed stage IV melanoma.
    4. Known with symptomatic brain metastasis and at time of randomization being radiologically progressive, with or without symptomatology.
    5. Symptomatic brain metastases are defined as cerebral metastases that based on their location and size can be related to clinical symptoms (e.g. headache, seizures, weakness).
    6. At least one radiologic new lesion in the brain by MRI, which should be measurable by RANO-BM criteria (longest diameter ≥ 10 mm and perpendicular diameter ≥ 5 mm). Lesions with prior local treatment (i.e., SRT or surgical resection) can be considered measurable if there has been demonstrated progression since the time of local treatment. Leptomeningeal involvement is allowed, but could not be used as target lesion.
    7. Clinically symptomatic brain metastases may be treated locally (i.e. SRT or surgical resection) if there is at least one other untreated lesion present that meets inclusion criterion #6.
    8. Known BRAF-status of primary melanoma or metastatic lesion.
    9. Subjects must be treatment-naive to nivolumab and ipilimumab. (also as adjuvant treatment)
    10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.(22)
    11. Subjects must have adequate organ function as defined by the following laboratory values (determined within 28 days prior to randomization/registration):
    • White blood cells (WBC) ≥ 2000 /µL
    • Absolute neutrophil count (ANC) ≥ 1500 /µL
    • Platelets ≥ 100 x103 /µL
    • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L
    • Serum creatinine ≤ 1.5 times upper limit of normal (ULN) or creatinine clearance > 40 ml/min (using the Cockcroft-Gault formula)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times ULN
    • Bilirubin ≤ 1.5 times ULN (Except patient with Gilbert Syndrome, who can have total bilirubin ≤ 3.0 mg/dL)
    • LDH < 2 times ULN
    12. Women of childbearing potential (WOCBP) should have a negative urine or serum pregnancy test within 24 hours prior to receiving the first administration of nivolumab/ipilimumab. Women with non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year.
    13. WOCBP and men who are sexually active with WOCBP must agree to use appropriate method(s) of contraception. (see section 5.2)

    E.4Principal exclusion criteria
    1. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 antibody. (also as adjuvant treatment). Prior treatment with anti-CTLA-4 antibodies (also adjuvant treatment).
    2. Subjects who have not recovered to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 1 or better from adverse events due to previous cancer therapy.
    3. Evidence for an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
    4. Treatment with corticosteroids in an increasing dosage in the 7 days prior to the first administration of nivolumab/ipilimumab. (A stable or decreasing dosage of ≤ 4 mg dexamethasone or equivalent is allowed. In addition, inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease.)
    5. Previous malignancies (except non-melanoma skin cancers, in situ bladder cancer, gastric or colon cancers, cervical cancers/dysplasia or breast carcinoma in situ) unless a complete remission was achieved at least 1 year prior to study entry and no additional therapy is required or anticipated to be required during the study period.
    6. Previous severe hypersensitivity reaction to treatment with another monoclonal antibody, or known hypersensitivity to study drugs components.
    7. A positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
    8. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
    9. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the patients to receive protocol therapy.
    10. A known psychiatric or substance abuse disorder that could interfere with cancer therapy.
    11. Women of childbearing potential with a positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab/ipilimumab.
    12. Breastfeeding women.
    13. Inability to comply with other requirements of the protocol.

    E.5 End points
    E.5.1Primary end point(s)
    Main endpoint of this study is the best overall response rate (BORR) of all previously determined target lesions in the brain, which will be determined according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After all patients have finished treatment in this trial.
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints that will be determined are: duration of response (DOR), time to development of new brain metastases in responding patients, progression-free survival, and overall survival.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After all patients have finished treatment in this trial.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 No
    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 trial1
    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 concerned14
    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
    The last visit of hte last subject undergoing this trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 35
    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 state70
    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)
    Standard of care
    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 Decision2015-09-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-05-30
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