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    Summary
    EudraCT Number:2016-004989-25
    Sponsor's Protocol Code Number:INCAGN1876-201
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-07-11
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2016-004989-25
    A.3Full title of the trial
    A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of INCAGN01876 in Combination With Immune Therapies in Subjects With Advanced or Metastatic Malignancies.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study exploring the safety, tolerability, and efficacy of INCAGN01876 in combination with immune therapies in subjects with advanced or metastatic malignancies.
    A.4.1Sponsor's protocol code numberINCAGN1876-201
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03126110
    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 SponsorIncyte Biosciences International Sàrl
    B.1.3.4CountrySwitzerland
    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 supportIncyte Biosciences International Sàrl
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIncyte Biosciences International Sàrl
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street Address1, route de la Corniche
    B.5.3.2Town/ cityEpalinges
    B.5.3.3Post code1066
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobalmedinfo@incyte.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 INCAGN01876
    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 INNnot yet availble
    D.3.9.3Other descriptive nameINCAGN01876
    D.3.9.4EV Substance CodeSUB187157
    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 5 mg/ml concentrate for solution for infusion
    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.3.4Pharmaceutical 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.3.9.4EV 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.IMP: 3
    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 10 mg/mL concentrate for solution for infusion
    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.3.4Pharmaceutical 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.3.9.4EV 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.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
    Ph1: adv. or metast. cervical cancer, endometrial cancer, gastric cancer, hepatocellular carcinoma, melanoma, Merkel cell carcinoma, mesothelioma, MSI-H colorectal cancer, non–small cell lung cancer, ovarian cancer, squamous cell carcinoma of the head and neck (SCCHN), small cell lung cancer, renal cell carcinoma, triple-negative breast cancer, urothelial carcinoma or others.
    Ph2: adv. or metast. cervical cancer, gastric cancer, SCCHN, PD-1 refractory SCCHN, and PD-1 or PD-L1 relapsed melanoma
    E.1.1.1Medical condition in easily understood language
    melanoma, mesothelioma, cervical, gastric, liver, skin, colorectal, lung, ovarian, head and neck, kidney, breast and bladder 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 PT
    E.1.2Classification code 10041067
    E.1.2Term Small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10014733
    E.1.2Term Endometrial cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10027407
    E.1.2Term Mesothelioma malignant
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064467
    E.1.2Term Urothelial carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027150
    E.1.2Term Melanoma malignant
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064025
    E.1.2Term Merkel cell carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10017758
    E.1.2Term Gastric cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10008229
    E.1.2Term Cervical cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 11.0
    E.1.2Level HLT
    E.1.2Classification code 10038408
    E.1.2Term Renal cell carcinomas
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061451
    E.1.2Term Colorectal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10075566
    E.1.2Term Triple negative breast cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10033128
    E.1.2Term Ovarian cancer
    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
    - Phase 1: To evaluate the safety, tolerability, and DLTs of INCAGN01876 in combination with immune therapies and to define the RP2D(s) of INCAGN01876 when given in combination with immune therapies.
    - Phase 2: To evaluate the efficacy of INCAGN01876 when given in combination with immune therapies by assessing ORR per RECIST v1.1.
    E.2.2Secondary objectives of the trial
    Phase 1 and Phase 2:
    • To evaluate the efficacy of INCAGN01876 when given in combination with immune therapies by assessing ORR, DOR, DCR, duration of disease control, and PFS per RECIST v1.1 and mRECIST v1.1.
    • To evaluate the efficacy of INCAGN01876 when given in combination with immune therapies with respect to 1-year and 2-year OS.
    • To evaluate the safety and tolerability of INCAGN01876 when given in combination with immune therapies.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Note: Due to space limitation in this window, a restricted set of subject inclusion criteria are presented below. The complete and detailed criteria are listed in the protocol.
    • Locally advanced or metastatic disease; locally advanced disease must not be amenable to resection with curative intent.
    • Phase 1: Subjects with advanced or metastatic cervical cancer, endometrial cancer, gastric cancer (including stomach, esophageal, and GEJ), HCC, melanoma (excluding uveal melanoma), Merkel cell carcinoma, mesothelioma, MSI-H CRC, NSCLC, ovarian cancer, SCCHN, SCLC, RCC, TNBC, and urothelial carcinoma (or alternative tumor types with medical monitor approval).
    • Phase 1: Subjects who have disease progression after treatment with available therapies that are known to confer clinical benefit, or who are intolerant to treatment, or who refuse standard treatment. There is no limit to the number of prior treatment regimens.
    • Phase 2: Subjects with advanced or metastatic cervical cancer, gastric cancer (including stomach, esophageal, and GEJ), SCCHN, PD-1 refractory SCCHN, or PD-1 or PD-L1 relapsed melanoma.
    − For subjects with cervical cancer: should have histologically confirmed squamous cell carcinoma of the cervix.
    − For subjects with gastric cancer: adenocarcinoma of the stomach, esophagus, or GEJ.
    − For subjects with SCCHN: histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Note: Should consent to have tumor evaluated for HPV and Epstein-Barr virus (EBV) status of the tumor (per local institutional testing), or have documentation of HPV and EBV tumor status. Note: Should have received only 1 prior chemotherapy regimen for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy). Adjuvant regimens given within 6 months of screening would be counted as first-line therapy. Prior chemotherapy regimen should have been a platinum-containing regimen. Note (Stage 2 only): Should have progressive disease per RECIST v1.1 during or within 6 months after treatment with a platinum-containing regimen. The platinum based therapy must be the last therapy the subject received before enrollment.
    -For subjects with PD-1 refractory SCCHN: histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx.
    Note: Should consent to have tumor evaluated for HPV and EBV status of the tumor(per local institutional testing), or have documentation of HPV and EBV tumor status.
    Note: PD-1 refractory SCCHN is defined as meeting all of the following criteria:
    i. Progressive disease per RECIST v1.1 as best overall response to treatment with an anti PD-1 containing regimen that is confirmed at least 4 weeks (no less than28 days) later.
    ii. Progressive disease should be at least 12 weeks from first dose of anti–PD-1 therapy and confirmed 4 weeks (no less than 28 days) later.
    iii. Should have received prior treatment with anti−PD-1 therapy for advanced or metastatic disease.
    iv. Should have received at least 2 doses of a prior anti–PD-1 containing regimen.
    v. The PD-1 therapy must be the last therapy the subject received before enrollment.
    − Tumor biopsy sample collection
    i. For subjects in the biopsy cohort: willingness to undergo pretreatment and on treatment tumor biopsies (core or excisional). Must have cervical cancer, endometrial cancer, gastric cancer (including stomach, esophageal and GEJ), SCCHN, PD-1 refractory SCCHN, PD-1 or PD-L1 relapsed melanoma (excluding uveal melanoma). Note: A baseline biopsy obtained for other purposes before signing consent may be used if the subject has not had any intervening systemic therapy from the time of the biopsy to the start of treatment (ie, Cycle 1 Day 1). Note: Subjects with cervical cancer, gastric cancer and SCCHN (excluding subjects with PD-1 refractory SCCHN) should not have received prior treatment with an immune therapy.
    ii For subjects in tumor-specific cohorts: willingness to undergo pretreatment tumor biopsy (core or excisional).
    Note: A baseline biopsy obtained for other purposes before signing consent may be used if the subject has not had any intervening systemic therapy from the time of the biopsy to the start of study treatment (ie, Cycle 1 Day 1).
    Note: De-identified pathology reports should be provided to the sponsor for confirmation of tumor tissue within the biopsy sample prior to enrollment.
    - For subjects with PD-1 or PD-L1 relapsed melanoma: mucosal or cutaneous melanoma is acceptable; however, subjects with uveal melanoma are excluded. Subjects should have documented BRAF mutation status or consent to BRAF mutation testing during the screening period. BRAF mutation status determined as part of a panel of genetic tests performed in a gene expression analysis will also satisfy the inclusion criterion for BRAF mutation testing.
    E.4Principal exclusion criteria
    • Laboratory and medical history parameters not within the Protocol-defined range.
    − Absolute neutrophil count < 1.0 × 10^9/L
    − Platelets < 75 × 10^9/L
    − Hemoglobin < 9 g/dL or < 5.6 mmol/L
    − Serum creatinine > 1.5 × institutional upper limit of normal (ULN), OR measured or calculated creatinine clearance < 50 mL/min for subjects with creatinine levels > 1.5 × ULN.
    − Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≥ 2.5 × ULN.
    − Total bilirubin ≥ 1.2 × ULN unless conjugated bilirubin ≤ ULN (conjugated bilirubin only needs to be tested if total bilirubin exceeds ULN). If there is no institutional ULN, then direct bilirubin must be < 40% of total bilirubin.
    − International normalized ratio, prothrombin time, or activated partial thromboplastin time > 1.5 × ULN.
    • Prior treatment with any TNFSF agonist (eg, glucocorticoid-induced tumor necrosis factor receptor [GITR], OX40, 4-1BB/CD137, CD27, etc), for any indication.
    • Transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors within 14 days before study Day 1.
    • Receipt of anticancer medications or investigational drugs within the following intervals before the first administration of study drug:
    − ≤ 14 days for chemotherapy, targeted small molecule therapy, or radiation therapy. Note: Subjects must not have had radiation pneumonitis as a result of treatment. A 1-week washout is permitted for palliative radiation to non–central nervous system (CNS) disease with medical monitor approval. Note: Bisphosphonates and denosumab are permitted concomitant medications.
    − ≤ 28 days for prior immune therapy or persistence of active cellular therapy (ie, chimeric antigen receptor T-cell therapy; other cellular therapies must be discussed with medical monitor to determine eligibility).
    − ≤ 28 days for a prior monoclonal antibody used for anticancer therapy with the exception of denosumab.
    − ≤ 7 days for immune-suppressive–based treatment for any reason. Note: Use of inhaled or topical steroids or corticosteroid use for radiographic procedures is permitted. Note: Must not require chronic use of corticosteroids. The use of physiologic corticosteroid replacement therapy may be approved after consultation with the medical monitor.
    − ≤ 28 days or 5 half-lives (whichever is longer) before the first dose for all other investigational agents or devices. For investigational agents with long half-lives (eg, > 5 days), enrollment before the fifth half-life requires medical monitor approval.
    • Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior immune therapy) and/or complications from prior surgical intervention before starting therapy Note: Subjects with stable chronic conditions (≤ Grade 2) not expected to resolve (such as neuropathy and alopecia) are exceptions and may enroll. Note: Subjects with a history of any grade immune-related ocular AE (eg, episcleritis, scleritis, uveitis) will be excluded. Note: Subjects with a history of a Grade 3 or higher immune-related AE from prior immunotherapies are excluded from the dose escalation portion of the study.
    • Active autoimmune disease that required systemic treatment in the past (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Note: Subjects who have not required systemic treatment in the past 2 years should discuss their case with medical monitor to determine eligibility. Note: Subjects with hyper/hypothyroidism, vitiligo, controlled asthma, Type I diabetes, Graves' disease, or Hashimoto's disease are eligible to participate. Note: Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) are not considered a form of systemic treatment and are allowed.
    • Known active CNS metastases and/or carcinomatous meningitis. Note: Subjects with previously treated brain metastases may participate provided that they are stable (without evidence of progression by imaging for at least 28 days before the first dose of study drug and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases or CNS edema, and have not required steroids for at least 7 days before the first dose of study drug.
    • Evidence of active, noninfectious pneumonitis or history of interstitial lung disease.
    • History or presence of an abnormal electrocardiogram that, in the investigator's opinion, is clinically meaningful.
    • Evidence of hepatitis B virus or hepatitis C virus infection or risk of reactivation.
    • Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies).
    E.5 End points
    E.5.1Primary end point(s)
    - Phase 1: Safety and tolerability (frequency, duration, and severity)
    - Phase 2: ORR, defined as the percentage of subjects having CR or PR, will be determined by investigator assessment of radiographic disease assessments per RECIST v1.1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    up to end of study
    E.5.2Secondary end point(s)
    • ORR, defined as the percentage of subjects having CR or PR, will be determined by investigator assessment of radiographic disease assessments per RECIST v1.1 and mRECIST v1.1.
    • DOR, defined as the time from the earliest date of disease response (CR or PR) until earliest date of disease progression or death due to any cause, if occurring sooner than progression, will be determined by investigator assessment of radiographic disease assessment per RECIST v1.1 and mRECIST v1.1.
    • DCR, defined as the percentage of subjects having CR, PR, or stable disease (SD), will be determined by investigator assessment of radiographic disease assessments per RECIST v1.1 and mRECIST v1.1.
    • Duration of disease control (CR, PR, and SD) as measured from first report of SD or better until disease progression or death from any cause, if occurring sooner than progression, will be determined by investigator assessment of radiographic disease per RECIST v1.1 and mRECIST v1.1.
    • PFS, defined as the time from the start of combination therapy until the earliest date of disease progression or death due to any cause, if occurring sooner than progression, as determined by investigator assessment of objective radiographic disease assessments per RECIST v1.1 and mRECIST v1.1.
    • OS determined from the start of combination therapy until death due to any cause. Survival analyses will occur at 1-year, 2-years, and at the end of the study.
    • Safety and tolerability will be assessed by monitoring frequency, duration, and severity of AEs.
    E.5.2.1Timepoint(s) of evaluation of this end point
    up to end of study
    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 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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase 1/2 study exploring safety, tolerability and efficacy
    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 Information not present in EudraCT
    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 trial7
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    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
    Australia
    Belgium
    Italy
    Spain
    United States
    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 years2
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    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: 225
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 225
    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 state72
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 176
    F.4.2.2In the whole clinical trial 450
    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 (Subjects may continue to receive study treatment as long as they are deriving benefit and have not met any of the protocol-defined conditions for treatment withdrawal, or for up to 24 months from the first dose of study treatment, whichever occurs first.)
    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 Decision2017-09-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-11-09
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