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    Summary
    EudraCT Number:2019-004542-15
    Sponsor's Protocol Code Number:SGN22E-003
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-08-07
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2019-004542-15
    A.3Full title of the trial
    An open-label, randomized, controlled phase 3 study of enfortumab vedotin
    in combination with pembrolizumab versus chemotherapy alone in
    previously untreated locally advanced or metastatic urothelial cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open-label clinical trial evaluating enfortumab vedotin in combination
    with pembrolizumab versus chemotherapy alone in previously untreated
    locally advanced or metastatic urothelial cancer
    A.4.1Sponsor's protocol code numberSGN22E-003
    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 SponsorSeattle Genetics, 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 supportSeattle Genetics Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSeattle Genetics Trial Information Support
    B.5.2Functional name of contact pointSeattle Genetics Trial Information
    B.5.3 Address:
    B.5.3.1Street Address21823 30th Drive SE
    B.5.3.2Town/ cityBothell
    B.5.3.3Post codeWA 98021
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1866333 7436
    B.5.6E-mailEU-Regulatory@seagen.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.3.1Product nameEnfortumab vedotin
    D.3.2Product code ASG-22CE
    D.3.4Pharmaceutical form Powder for 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 INNENFORTUMAB VEDOTIN
    D.3.9.2Current sponsor codeASG-22CE
    D.3.9.4EV Substance CodeSUB185524
    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 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.3.1Product namePembrolizumab
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form 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 INNPembrolizumab
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Cisplatin
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    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.3.1Product nameCisplatin
    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 INNCISPLATIN
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/l milligram(s)/litre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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) No
    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 No
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Carboplatin
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    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.3.1Product nameCarboplatin
    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.3.9.3Other descriptive nameCARBOPLATIN
    D.3.9.4EV Substance CodeSUB06614MIG
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Gemcitabine
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Limited
    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.3.1Product nameGemcitabine
    D.3.4Pharmaceutical form Powder 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 INNGEMCITABINE
    D.3.9.1CAS number 95058-81-4
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38
    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) No
    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 No
    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
    Urothelial cancer
    E.1.1.1Medical condition in easily understood language
    Urothelial cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10046714
    E.1.2Term Urothelial carcinoma bladder
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10046723
    E.1.2Term Urothelial carcinoma ureter
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10046728
    E.1.2Term Urothelial carcinoma urethra
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To compare PFS between the experimental arm (enfortumab vedotin + pembrolizumab [Arm A] and the control arm (gemcitabine + cisplatin or carboplatin [Arm B]) by blinded independent central review (BICR)
    - To compare overall survival (OS) between the experimental arm (Arm A) and the control arm (Arm B)
    E.2.2Secondary objectives of the trial
    To evaluate the ORR between the experimental arm (Arm A) and the
    control arm (Arm B)
    - To evaluate the DOR between the experimental arm (Arm A) and the
    control arm (Arm B)
    - To evaluate the disease control rate (DCR) between the experimental
    arm (Arm A) and the control arm (Arm B)
    - To evaluate PFS per investigator assessment between the experimental
    arm (Arm A) and the control arm (Arm B)
    - To assess the impact of study treatment on quality of life (QOL), and
    symptoms including pain from the subject perspective
    - To evaluate the safety profile of each treatment regimen
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subjects must have histologically documented, unresectable locally advanced or metastatic urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with squamous or sarcomatoid differentiation or mixed cell types are eligible.

    2. Subjects must have measurable disease by investigator assessment according to RECIST v1.1.
    a. Subjects with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy

    3. Subjects must not have received prior systemic therapy for locally advanced or metastatic urothelial carcinoma with the following exceptions:
    a. Subjects that received neoadjuvant chemotherapy with recurrence >12 months from completion of therapy are permitted
    b. Subjects that received adjuvant chemotherapy following cystectomy with recurrence >12 months from completion of therapy are permitted

    4. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, in the investigator’s judgement.
    a. Subjects will be considered cisplatin-ineligible, and will receive carboplatin, if they meet at least one of the following criteria:
    i. GFR <60 mL/min but ≥30 mL/min (measured by the Cockcroft-Gault formula, Modification of Diet in Renal Disease [MDRD] or 24-hour urine)
    · Subjects with a GFR ≥50 mL/min and no other cisplatin ineligibility criteria may be considered cisplatin-eligible based on the investigator’s clinical judgement
    ii. ECOG or WHO performance status of 2 (refer to Inclusion 7 for additional criteria for ECOG 2 subjects)
    iii. NCI CTCAE Grade ≥2 audiometric hearing loss
    iv. NYHA Class III heart failure

    5. Subjects must be age 18 years or older

    6. Archival tumor tissue comprising muscle-invasive urothelial carcinoma or a biopsy of metastatic urothelial carcinoma must be provided for PD-L1 testing prior to randomization. If adequate archival tumor sample is not available, or evaluable, a new biopsy sample may be performed.

    7. Subjects must have an ECOG Performance Status score of 0, 1, or 2.
    a. Subjects with ECOG performance status of 2 must additionally meet the following criteria:
    i. Hemoglobin ≥10 g/dL
    ii. GFR ≥50 mL/min
    iii. May not have NYHA Class III heart failure

    8. Subjects must have adequate hematologic and organ function as defined by the baseline laboratory values in Table 3 (see protocol)

    9. Female subjects of childbearing potential must meet the following
    conditions:
    · Agree not to try to become pregnant during the study and for at least 6
    months after the final dose of study drug.
    · Must have a negative urine or serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) within 1 day prior to administration of the study drug.
    . Female subjects with false positive results and documented verification of negative pregnancy status are eligible for participation.
    · If heterosexually active must consistently use highly effective methods of birth control, with a failure rate of less than 1% starting at screening, throughout the study period, and for at least 6 months after the final
    dose of study drug. Female subjects must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final dose of study drug.
    10. Male subjects who can father children, must meet the following
    conditions:
    · Must not donate sperm starting at screening and throughout the study
    period, and for at least 6 months after the final dose of study drug. Male subjects will be informed about the negative risk to reproductive function and fertility from the study treatment. Prior to treatment male
    subjects should be advised to seek information on fertility preservation
    and sperm cryoconservation.
    · Must consistently use highly effective methods of birth control, with a failure rate of less than 1% starting at screening and continue throughout study period and for at least 6 months after the final dose of study drug.
    · Male subjects with a pregnant or breastfeeding partner(s) must consistently use one of 2 contraception options for preventing secondary exposure to seminal fluid for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final dose of study drug.
    E.4Principal exclusion criteria
    1. Subjects who have previously received enfortumab vedotin or other MMAE-based ADCs.
    2. Subjects who have received prior treatment with a PD-(L)-1 inhibitor for any malignancy, including earlier stage UC, defined as a PD-1 inhibitor or PD-L1 inhibitor.
    3. Subj. who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor.
    4. Subj. who have received anti-cancer treatment with chemotherapy, biologics, or investigational agents not otherwise prohibited by exclusion criterion 1-3 that is not completed 4 weeks prior to first dose of study treatment.
    5. Subj. with uncontrolled diabetes.
    6. Subj. with an estimated life expectancy <12 weeks
    7. Subj. with ongoing sensory or motor neuropathy Grade 2 or higher.
    8. Subj. with active CNS metastases. Subjects with treated CNS metastases are permitted on study if all of the following are true: a) CNS metastases have been clinically stable for at least 4 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis; b) the subject is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment); c) subject does not have leptomeningeal disease.
    9. Subj. with ongoing clinically significant toxicity associated with prior treatment (including radiotherapy or surgery) that has not resolved to ≤ Grade 1 or returned to baseline.
    10. Currently receiving systemic antimicrobial treat. for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.
    11. Subj. who have a active known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Testing for hepatitis B and hepatitis C is required if mandated by country health authority. Subjects who have been curatively treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
    12. Has a known history of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by the local health authority.
    13. Subj. with conditions requiring high doses of steroids (>10 mg/day of prednisone or equivalent) or other immunosuppressive medications are excluded. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. Physiologic replacement doses of corticosteroids are permitted for subjects with adrenal insufficiency.
    14. Subj. with a history of another invasive malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy (eligible exceptions see protocol).
    15. Subj. with a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with NYHA Class IV within 6 months prior to randomization.
    16. Subj. who have received radiotherapy within 2 weeks prior to randomization.
    17. Subj. who have received major surgery (defined as requiring general anesthesia and >24-hour inpatient hospitalization) within 4 weeks prior to randomization.
    18. Subj. with known severe (≥ Grade 3) hypersensitivity to any excipient contained in the drug formulations of enfortumab vedotin, pembrolizumab, the platinum agent selected by the investigator or gemcitabine.
    19. Subj. with active keratitis or corneal ulcerations.
    20. History of autoimmune disease that has required systemic treatment in the past 2 years.
    a. Replacement therapy (e.g., thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
    b. Brief (<7 days) use of systemic corticosteroids is allowed when use is considered standard of care.
    c. Subjects with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy will not be excluded.
    d. Subj. requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections will not be excluded.
    e. Subj. with hypothyroidism that is stable with hormone replacement or Sjögren's synd. will not be excluded.
    21. Subj. with a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
    22. Subj. who have received a prior allogeneic stem cell or solid organ transplant.
    23. Subj. who have received a live attenuated vaccine within 30 days prior to randomization.
    24. Subj. with active tuberculosis.
    25. Subj. with another underlying medical condition that, in the opinion of the investigator, would impair the ability of the subject to receive or tolerate the planned treatment and follow-up; any known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.
    E.5 End points
    E.5.1Primary end point(s)
    ● PFS per RECIST v1.1 by BICR
    ● OS
    E.5.1.1Timepoint(s) of evaluation of this end point
    Response assessments should be performed every 9 weeks (±1-week) timed from the randomization date until 18 months after randomization, then every 12 weeks (±1-week) thereafter.
    Survival status will be updated every 12 weeks (±1-week) until death, withdrawal of consent, or study closure, whichever occurs first.
    E.5.2Secondary end point(s)
    ● ORR per RECIST v1.1 by BICR
    ● ORR per RECIST v1.1 by investigator assessment
    ● DOR per RECIST v1.1 by BICR
    ● DOR per RECIST v1.1 by investigator assessment
    ● DCR per RECIST v1.1 by BICR
    ● DCR per RECIST v1.1 by investigator assessment
    ● PFS per RECIST v1.1 by investigator assessment
    ● Change from baseline in patient reported outcome (PRO) assessments of the EuroQOL 5-dimensions (EQ-5D-5L), European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30), and Brief Pain Inventory – Short Form (BPI-SF)
    ● Type, incidence, relatedness, severity and seriousness of AEs
    ● Type, incidence and severity of laboratory abnormalities
    ● Treatment discontinuation rate due to AEs
    E.5.2.1Timepoint(s) of evaluation of this end point
    Response assessments should be performed every 9 weeks (±1-week) timed from the randomization date until 18 months after randomization, then every 12 weeks (±1-week) thereafter.
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Biomarker
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    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) Yes
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    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
    Belgium
    Canada
    Denmark
    France
    Germany
    Hungary
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Russian Federation
    Spain
    Taiwan
    United Kingdom
    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
    Subjects will remain on study until death, study closure, or withdrawal of consent, whichever occurs first (survival follow-up every 12 weeks).
    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 months10
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    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: 684
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 76
    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 state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 320
    F.4.2.2In the whole clinical trial 760
    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 Decision2020-08-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-09-24
    P. End of Trial
    P.End of Trial StatusOngoing
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