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    EudraCT Number:2012-002206-52
    Sponsor's Protocol Code Number:CD-ON-MEDI4736-1108
    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:2012-11-22
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2012-002206-52
    A.3Full title of the trial
    A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 in Subjects with Advanced Solid Tumors
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 in Subjects with Advanced Solid Tumors
    A.4.1Sponsor's protocol code numberCD-ON-MEDI4736-1108
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01693562
    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 SponsorMedImmune
    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 supportMedImmune
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstra Zeneca
    B.5.2Functional name of contact pointClinical Trial Transparency
    B.5.3 Address:
    B.5.3.1Street AddressKarlebyhus, Astraallén
    B.5.3.2Town/ citySödertälje
    B.5.3.3Post code151 85
    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 nameDurvalumab
    D.3.2Product code MEDI4736
    D.3.4Pharmaceutical form Lyophilisate for solution 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 INNdurvalumab
    D.3.9.1CAS number 1428935-60-7
    D.3.9.2Current sponsor codeMEDI4736
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Advanced Solid Tumors
    E.1.1.1Medical condition in easily understood language
    Dose escalation: lung, colon, kidney, skin
    Dose expansion: lung, cutaneous melanoma, uveal melanoma, liver,
    gastroesophageal, pancreatic adenocarcinoma, head and neck, triple
    neg. breast, bladder
    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
    Dose-escalation phase: to determine the maximum tolerated dose (MTD) or optimal biological dose (OBD), and the safety profile of MEDI4736 in subjects with advanced solid tumors.
    Dose-expansion phase:
    1. To determine the safety profile of MEDI4736 in subjects with advanced cutaneous melanoma, uveal melanoma, hepatocellular carcinoma (HCC), squamous cell carcinoma of the head and neck (SCCHN), NSCLC squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, triple negative breast cancer (TNBC), pancreatic adenocarcinoma etc (Refer to protocol section 2.1 for more information).
    2. To evaluate the antitumor activity of MED14736 in subjects with non-squamous NSCLC who have received 2 or more prior lines of therapy and subjects with squamous NSCLC who have received 1 prior line of therapy and 2 or more prior lines of therapy.
    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    1) To describe the pharmacokinetics (PK) of MEDI4736
    2) To determine the immunogenicity (IM) of MEDI4736
    3) To evaluate the antitumor activity of MEDI4736
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Written informed consent.
    Dose-escalation phase: histologically-or cytologically- confirmed advanced melanoma, renal cell carcinoma, non-small cell lung cancer, or colorectal cancer that is refractory to standard therapy and for which no standard therapy exists.
    Dose-expansion phase: histologically-or cytologically-confirmed advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous and non-squamous, gastroesophageal cancer, TNBC, or pancreatic adenocarcinoma, UBC, GBM, epithelial ovarian cancer, soft tissue sarcoma, SCLC, MSI-high cancers, HPV-positive cancers, or nasopharyngeal carcinoma.
    HCC subjects must be of Child-Pugh class A (not amenable to or refractory to locoregional therapy). Subjects with HCC associated with hepatitis B virus must be receiving adequate antiviral therapy.
    Subjects with histologically or cytologically documented NSCLC must present with Stage IIIB/ Stage IV disease, or with recurrent or progressive disease following multimodal therapy for locally advanced disease (refer to protocol for further details).
    Subjects with SCCHN must have disease that is either metastatic or recurrent and deemed to be incurable by the investigator.
    MSI-high cancers must have defective DNA mismatch repair by EITHER high-frequency microsatellite instability with changes detected in 2 or more panels of microsatellite markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) OR immunohistochemical analysis demonstrating absence of protein expression of any 1 or more of the following proteins: MLH1, MSH2, MSH6, PMS2.
    Subjects with HPV-positive cancers are eligible if they have a confirmed HPV positive tumor by local laboratory.
    GBM cohort: Subjects with GBM must not have significant edema or shift from midline by intracranial imaging, or be symptomatic due to edema. A minimum of 10 subjects without O6-methylguanine-DNA methyltransferase promoter methylation will be enrolled in the GBM cohort. Epithelial ovarian cancer cohort: A minimum of 10 subjects with platinum sensitivity will be enrolled in the ovarian cancer cohort.
    If an approved first-line standard therapy is available, subjects must have failed, be intolerant to, be ineligible for, or have refused treatment
    Progressive disease as assessed by the investigator or treatment naïve at the time of study entry.
    Tumoral PD-L1 expression requirements are as follows:
    •HCC, gastroesophageal cancer, TNBC, GBM, ovarian cancer, soft tissue sarcoma, SCLC, HPV-positive cancers, pancreatic adenocarcinoma, and nasopharyngeal carcinoma dose-expansion cohorts: after the first 20-40 subjects in each cohort are enrolled, additional subjects in the applicable cohorts may be required to have tumoral PD-L1 expression as determined by prospective testing prior to enrollment.
    NSCLC (squamous and non-squamous) dose-expansion cohorts:
    •Non-squamous NSCLC: all remaining subjects to be enrolled will be required to have tumoral PD-L1 expression as determined by prospective testing prior to enrollment.
    •Squamous NSCLC: A minimum of 10 subjects in the first-line therapy cohort, and a minimum of 35 subjects in each of the second-line therapy and third-line or greater therapy cohorts will be required to have tumoral PD-L1 expression as determined by prospective testing prior to enrollment.

    Age ≥ 18 years at time of study entry.
    Effective contraception (refer to protocol for further details).
    Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
    Adequate organ and marrow function.
    Subjects must have at least 1 measurable lesion per RECIST v1.1 guidelines or per RANO guidelines for subjects with GBM.
    Available unstained archived tumor tissue sample..
    Life expectancy ≥ 16 weeks
    At least 1 lesion amenable to biopsy (dose-expansion phase only)
    Willingness to provide consent for biopsy samples (dose-expansion phase only).
    Histologically/cytologically confirmed advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous and nonsquamous histology, gastroesophageal cancer, TNBC, or pancreatic adenocarcinoma (dose-exploration cohort).
    E.4Principal exclusion criteria
    Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
    Receipt of any immunotherapy, BRAF inhibitor (in cutaneous melanoma and uveal melanoma subjects), or investigational anticancer therapy within 4 weeks prior to the first dose of MEDI4736; in the case of MAbs, 6 weeks prior to the first dose of MEDI4736.
    Any prior Grade ≥ 3 irAE while receiving immunotherapy.
    For all subjects: prior exposure to any anti-PD-1 or anti-PD-L1 antibody. For UBC cohort: prior treatment with immunotherapy agents including, but not limited to, tumor necrosis factor receptor superfamily agonists or checkpoint inhibitors or natural killer (NK) cell inhibitors including agents targeting KIR, PD-1, PD-L1, CTLA-4, OX40, CD27, CD137 (4-1BB), CD357 (GITR), and CD40. Prior treatment with Bacillus
    Calmette-Guerin therapy is permitted.
    Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment.
    Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736.
    Active or prior documented autoimmune disease within the past 2 years
    Note: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
    Active or prior documented inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis).
    History of primary immunodeficiency.
    History of organ transplant that requires use of immunosuppressives.
    Known allergy or reaction to any component of the MEDI4736 formulation.
    Untreated CNS metastatic disease, leptomeningeal disease, or cord compression.
    Other invasive malignancy within 2 years except for noninvasive malignancies that have been surgically cured.
    Unresolved toxicities from prior anticancer therapy.
    Major surgical procedure (as defined by the investigator) within 30 days prior to the first dose of MEDI4736 or still recovering from prior surgery.
    Females who are pregnant or lactating.
    Uncontrolled intercurrent illness.
    Any condition that would interfere with evaluation of the investigational product or interpretation of subject safety or study results.
    Known history of tuberculosis.
    Known to be human immunodeficiency virus (HIV) positive.
    Hepatitis B or C infection.
    Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736.
    Subjects with pancreatic adenocarcinoma must not have more than 50% of the liver parenchyma replaced by tumour.
    Subjects with HCC must not have a history of bleeding from esophageal varices, unless the varices have been treated with no active bleeding within 30 days prior to the first dose of MEDI4736.
    Prior participation in clinical studies that include MEDI4736 alone or in combination, where the study has registrational intent and the analyses for the primary endpoint have not yet been completed.
    E.5 End points
    E.5.1Primary end point(s)
    Dose-escalation phase: evaluation of DLTs (dose-limiting toxicity), overall safety, and parameters related to the MTD (maximum tolerated dose) or OBD (optimal biological dose). The MTD evaluation will be based on the DLT Evaluable Population. The OBD will be determined based upon analysis of all available subject data, including safety, pharmacokinetic, pharmacodynamic, biomarker, and response data.
    Dose-expansion phase:
    Endpoints for safety profile - assessments of AEs, SAEs, laboratory evaluations, vital signs, and physical examinations.
    The primary endpoint for of the antitumor activity for the NSCLC and UBC cohorts is objective response (OR), which is defined as a best overall response (BoR) of CR or PR according to RECIST v1.1 as determined by BICR. BoR is defined as the best response (in the order of CR, PR, SD, PD, and not evaluable) among all overall responses recorded from the start of treatment until objective documentation of PD (per RECIST v1.1 as assessed by BICR), or the last evaluable disease assessment in the absence of PD prior to initiation of subsequent anticancer therapy or discontinuation from the study, whichever occurs first.
    The primary endpoint for UBC cohort in PD-L1-positive subgroup is considered to be met if the lower-limit of the exact 2-sided 95% CI for ORR excludes a historical response rate of 10% or less. ORR per BICR for the UBC cohort will be repeated for UBC subjects in PD-L1-positive FAS, PD-L1-negative FAS and FAS (regardless of PD-L1 status) enrolled in the entire study.
    For the dose-exploration cohort, the primary objective is to determine the safety profile of MEDI4736 in subjects with advanced cutaneous melanoma, uveal melanoma, HCC, SCCHN, NSCLC squamous histology, NSCLC non-squamous histology, gastroesophageal cancer, TNBC and pancreatic adenocarcinoma using a Q4W dosing schedule.
    Endpoints for safety profile including assessments of AEs, SAEs, laboratory evaluations, vital signs, and physical examinations will be summarized in the same manner as those described above for dose-expansion phase.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Continous through to 90 days after the last dose of MEDI4736
    E.5.2Secondary end point(s)
    1. Assessment of Pharmacokinetics
    2. Assessment of Immunogenicity
    3. Assessment of Antitumour activity
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to 90 days after the last dose of MEDI4736.
    2. Up to 6 months after the last dose of MEDI4736.
    3. Tumour efficacy evaluations and survivial status continue until withdrawal of consent or death.
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. 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 trial16
    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 EEA46
    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
    Korea, Republic of
    United Kingdom
    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
    The end of the study (“study completion”) is defined as the date of the last protocol-specified visit/assessment (including telephone contact) for the last subject in the study or the date the study is closed by the sponsor, which ever occurs first.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months10
    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: 521
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 801
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 264
    F.4.2.2In the whole clinical trial 1322
    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)
    Normal 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 Decision2012-11-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-02-28
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