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    Summary
    EudraCT Number:2012-003030-17
    Sponsor's Protocol Code Number:3475-002
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-01-08
    Trial results View 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 number2012-003030-17
    A.3Full title of the trial
    Randomized, Phase II Study of MK-3475 versus Chemotherapy in Patients with Advanced Melanoma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Patients will be randomly assigned to receive an experimental study medication (MK-3475) or a commonly used chemotherapy medication. The purpose of this study is learn more about the safety and effect of MK-3475 compared to other chemotherapy medication in patients who have skin cancer that has spread to other part of the body.

    A.4.1Sponsor's protocol code number3475-002
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlobal Clinical Trials Operations (GCTO)
    B.5.2Functional name of contact pointKellie Celentano
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive, PO Box 100
    B.5.3.2Town/ cityWhitehouse Station
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number00 1412650 8232
    B.5.5Fax number00 1908259 3791
    B.5.6E-mailkellie.celentano@merck.com
    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 No
    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.3.2Product code SCH 900475; MK-3475
    D.3.4Pharmaceutical form Powder for injection
    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 INNambrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeSCH 900475; MK-3475
    D.3.9.3Other descriptive nameAnti-PD-1 monoclonal antibody
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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) 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
    Advanced melanoma (unresectable or metastatic)
    E.1.1.1Medical condition in easily understood language
    Skin cancer that has spread other parts of the body
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10027480
    E.1.2Term Metastatic malignant melanoma
    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
    1) To evaluate the progression-free-survival (PFS) in patients with ipilimumab refractory advanced MEL receiving either MK-3475 or chemotherapy.

    Hypothesis: Administration of MK-3475 will result in a clinically meaningful improvement in PFS versus treatment with chemotherapy.

    2) To evaluate the overall survival (OS) in patients with ipilimumab refractory advanced MEL receiving either MK-3475 or chemotherapy.

    Hypothesis: Administration of MK-3475 will result in a clinically meaningful improvement in OS versus treatment with chemotherapy.
    E.2.2Secondary objectives of the trial
    1) To evaluate the overall response rate (ORR) in patients with ipilimumab refractory advanced MEL receiving either MK-3475 or chemotherapy.

    Hypothesis: Administration of MK-3475 will result in a clinically meaningful improvement in ORR versus treatment with chemotherapy.

    2) To evaluate the response duration in patients with ipilimumab refractory advanced MEL receiving either MK-3475 or chemotherapy.

    3) To evaluate OS, PFS, and ORR in the biomarker positive subgroup defined by PD-L1 expression level (cutoff point to be estimated from external data) receiving either MK-3475 or chemotherapy.

    4) To further characterize the PK profile of single agent MK-3475 at 2 mg/kg and 10 mg/kg.

    5) To evaluate safety, tolerability and adverse experience profile of single agent MK-3475 2 mg/kg and 10 mg/kg.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Patient must have a histologically or cytologically confirmed diagnosis of unresectable stage III or metastatic MEL not amenable to local therapy.
    • Patient may not have a diagnosis of uveal melanoma
    2) Patients must be refractory to ipilimumab, defined as (patients must meet all of the following criteria):
    • Received at least two doses of ipilimumab (minimum dose of 3 mg/kg given every 3 weeks)
    • Progressive disease (PD) after ipilimumab will be defined according to irRC (Appendix 6.6). The initial evidence of PD is to be confirmed by a second assessment, no less than four weeks from the date of the first documented PD, in the absence of rapid clinical progression (this determination is made by investigator; SPONSOR will collect imaging scans for retrospective analysis). Once PD is confirmed, initial date of PD documentation will be considered the date of disease progression.
    • Documented disease progression within 24 weeks of the last dose of ipilimumab. Patients who were re-treated with ipilimumab and patients who were on maintenance ipilimumab will be allowed to enter the trial as long as there is documented PD within 24 weeks of the last treatment date (with ipilimumab).
    • Ipilimumab does not need to be the last treatment prior to entering current trial as long as the patient meets the above described criteria
    3) Resolution/improvement of ipilimumab-related AEs (including irAEs) back to Grade 0-1 and ≤10 mg/day prednisone (or equivalent dose) for irAEs for at least two weeks prior to first dose of study drug.
    • No history of CTCAE Grade 4 irAEs from ipilimumab
    • No history of CTCAE Grade 3 requiring steroid treatment (>10 mg/day prednisone or equivalent dose) >12 weeks
    • Minimum of four weeks (wash out period) from the last dose of ipilimumab
    4) Patients must consent to provide a newly obtained tumor tissue/biopsy (or specimen obtained within 60 days prior to consenting) for biomarker analysis from a core or excisional biopsy of a tumor lesion not previously irradiated.
    • The patient must be able to undergo tumor biopsy
    • If a newly obtained biopsy is not feasible, the patient requires sponsor approval to be eligible
    5) BRAF V600E or V600K mutation status must be known at Screening. Patient with BRAF mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF and/or MEK inhibitor.
    6) Patient must have at least one radiologically measurable lesion as per RECIST 1.1 (Appendix 6.1) defined as a lesion that is 10mm in longest diameter or lymph node that is 15mm in short axis imaged by CT scan or MRI.
    7) Patient is ≥18 years of age on day of signing informed consent.
    8) Patient must have a performance status of 0 or 1 on the ECOG Performance Scale (Appendix 6.4).
    E.4Principal exclusion criteria
    1) Patient who has had chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or who has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics administered more than four weeks earlier.
    • The requirements for prior ipilimumab treatment are listed in Inclusion Criterion 2
    2) Patient who received ipilimumab only as an adjuvant therapy.
    3) Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug.
    4) Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study.
    5) Patient is on chronic systemic steroid therapy (>10 mg/day prednisone or equivalent) within two weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication. (Patients that are expected to require premedication with corticosteroid for MK-3475 will not be eligible for this study.)
    6) Patient has a known history of a hematologic malignancy, primary brain tumor or sarcoma, or of another primary solid tumor, unless the patient has undergone potentially curative therapy with no evidence of that disease for five years.
    • The time requirement for no evidence of disease for five years does not apply to the tumor for which a patient is enrolled in the study. The time requirement also does not apply to patients who underwent successful definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, breast cancer, or other in situ cancers.
    7) Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they meet the following criteria:
    • Inactive (without evidence of progression which is documented by CT or MRI within 4 weeks prior to the planned study treatment date), and
    • On ≤10 mg/day prednisone or equivalent for at least two weeks prior to the planned study treatment date
    8) Patient previously had a severe hypersensitivity reaction to treatment with another mAb.
    9) Patient has an active autoimmune disease or a history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement will not be excluded from the study.
    10) Patients who received treatment with live vaccines within 30 days prior to the first dose of study medication. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, BCG, and typhoid vaccine.
    11) Patient had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent.
    • Examples of PD-1 inhibitors (include, but are not limited to): MK-3475 (Merck); Nivolumab (also known as BMS-936558, MDX-1106, ONO-4538) (Bristol-Myers Squibb); Pidilizumab (CT-11) (Cure-Tech/Teva); and AMP-224 (Amplimmune)
    • Examples of PD-L1 inhibitors (include, but are not limited to): BMS-936559 (also known as MDX-1105) (Bristol-Myers Squibb); MPDL3280A (also known as RG7446) (Roche Genentech); and MEDI4736 (MedImmune)
    • Patients who have received carboplatin plus paclitaxel, paclitaxel alone, DTIC, or temozolomide for MEL prior to randomization will not be eligible to receive the same chemotherapy as study medication. Patients who received DTIC are not eligible to receive temozolomide (and vice versa). Patients who received carboplatin plus paclitaxel are not eligible to receive paclitaxel monotherapy. Patients who received abraxane are not eligible to receive paclitaxel.
    12) Patient has previously participated in Merck MK-3475 clinical trials.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free-survival; Overall survivall
    E.5.1.1Timepoint(s) of evaluation of this end point
    Progression-free-survival; Overall survivall
    E.5.2Secondary end point(s)
    Overall response rate; Response duration; Overall survival, progression-free-survival, and overall response rate in the biomarker positive subgroup
    E.5.2.1Timepoint(s) of evaluation of this end point
    Overall response rate; Response duration; Overall survival, progression-free-survival, and overall response rate in the biomarker positive subgroup
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    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 Yes
    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 Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Israel
    United States
    E.8.7Trial has a data monitoring committee Yes
    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 years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial 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: 255
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 255
    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 Yes
    F.3.3.4Nursing women Yes
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 271
    F.4.2.2In the whole clinical trial 510
    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)
    none
    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 Decision2012-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-01-31
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