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    EudraCT Number:2014-003295-23
    Sponsor's Protocol Code Number:D4193C00001
    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:2015-01-22
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2014-003295-23
    A.3Full title of the trial
    A Phase II, Multi-Center, Single-Arm, Global Study of MEDI4736 Monotherapy in Patients with Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This is a study of MEDI4736 monotherapy in patients with head and neck
    cancer, who have progressed during or after treatment with only 1 systemic
    palliative regimen for recurrent or metastatic disease that must have contained a
    platinum agent.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberD4193C00001
    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 SponsorAstraZeneca AB
    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 supportAstraZeneca AB
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    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 nameMEDI4736
    D.3.2Product code MEDI4736
    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 INNNot applicable
    D.3.9.1CAS number 1428935-60-7
    D.3.9.2Current sponsor codeMEDI4736
    D.3.9.3Other descriptive nameMEDI4736
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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. 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
    Recurrent or metastatic PD-L1-positive squamous cell carcinoma of the head and neck (SCCHN).
    E.1.1.1Medical condition in easily understood language
    Head and neck cancer.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10067821
    E.1.2Term Head and neck 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
    To assess the efficacy of MEDI4736 monotherapy in terms of objective response rate (ORR).
    E.2.2Secondary objectives of the trial
    To further assess the efficacy of MEDI4736 monotherapy in terms of duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
    To explore symptoms and health-related quality of life (QoL) in patients treated with MEDI4736 monotherapy using the EORTC 30-item core quality of life questionnaire, version 3 (QLQ-C30 v3) and the 35-item head and neck quality of life questionnaire (QLQ-H&N35) module.
    To assess the safety and tolerability profile of MEDI4736 monotherapy
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    AstraZeneca intends to perform genetic research in the MEDI4736 clinical development program to explore how genetic variations may affect the clinical parameters associated with this drug. Collection of DNA samples from populations with well-described clinical characteristics may lead to improvements in the design and interpretation of clinical trials and, possibly, to genetically guided treatment strategies.
    The objective of this research is to collect and store DNA, derived from a blood sample, for
    future exploratory research into genes/genetic variations that may influence response, ie,
    distribution, safety, tolerability, and efficacy of MEDI4736, and/or susceptibility to SCCHN.
    All enrolled patients who take part in the main study will be asked to participate in this genetic
    research. Participation is voluntary. For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described in the main body of the Clinical Study Protocol and provide informed consent for the genetic sampling and analyses.
    Blood samples will ideally be collected during the screening/baseline period. If for any reason
    the sample is not drawn during the screening/baseline period, it should be taken as soon as
    possible, but not later than the last study visit. Only 1 sample should be collected per patient for genetics during the study.
    E.3Principal inclusion criteria
    1.Age ≥18 years at the time of screening
    2.Written informed consent and any locally required authorization obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
    3.Histologically confirmed recurrent or metastatic SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) not amenable to therapy with curative intent (surgery or radiation therapy with or without chemotherapy). Patients who refuse radical resection are eligible.
    4.Tumor progression or recurrence during or after treatment with only 1 systemic palliative regimen for recurrent or metastatic disease that must have contained a platinum agent. Patients who have only received chemo-radiation with curative intent for treatment of their locally advanced disease or recurrent disease are not eligible.
    5.Able and willing to give valid written consent to provide newly acquired tumor tissue (preferred) or archival tissue (<3 years old) for the purpose of establishing PD-L1 status. Tumor lesions used for newly acquired biopsies should not be the same lesions used as RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy.
    6.Confirmed PD-L1–positive SCCHN by the Ventana SP263 assay on newly acquired tumor tissue (preferred) or archival tissue (<3 years old)
    If the patient's PD-L1 status has already been assessed using the analytically validated Ventana assay as a part of the screening process for another AstraZeneca/MedImmune study, this test result can be used for the determination of eligibility.
    Note: A positive PD-L1 sample for eligibility is defined by the presence of membrane staining of any intensity in ≥25% of tumor cells using the Ventana assay.
    7.World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment.
    8.At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines. Lesions in a previously irradiated field can be used as measurable disease provided that there has been demonstrated progression in the lesion.
    9.Patients must have no prior exposure to immune-mediated therapy, including other anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines. Prior exposure to other investigational agents may be permitted after discussion with the sponsor.
    10.Adequate organ and marrow function independent of transfusion for at least 7 days prior to screening and independent of growth factor support for at least 14 days prior to screening, defined as:
    - Hemoglobin ≥9 g/dL
    - Absolute neutrophil count ≥1500/mm3
    - Platelet count ≥100000/mm3
    - Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who will be allowed in consultation with their physician.
    - ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN
    - Calculated creatinine clearance ≥40 mL/min as determined by
    Cockcroft-Gault (using actual body weight)
    11.Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
    The following age-specific requirements apply:
    - Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and folliclestimulating hormone levels in the post-menopausal range for the institution.
    - Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral ophorectomy or hysterectomy).
    E.4Principal exclusion criteria
    1.Histologically confirmed squamous cell carcinoma of any other primary anatomic location in the head and neck , patients with squamous cell carcinoma of the head and neck of unknown primary, and non-squamous histologies (eg, nasopharynx or salivary gland); 2.Received more than 1 systemic palliative regimen for recurrent or metastatic disease; 3. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions is acceptable. Note: Local treatment of isolated lesions for palliative intent is acceptable (eg, local surgery or radiotherapy); 4.Prior
    randomization or treatment in a previous MEDI4736 and/or
    treme clinical study regardless of treatment arm assignment or
    receipt of any invest. anticancer therapy within 28 days or 5 half-lives, whichever is longer, prior to the first dose of study treatment; 5.Receipt of last dose of an approved (marketed) anticancer therapy within 21 days prior to the 1st dose of study treatm. If sufficient washout time has not occurred due to the schedule or PK properties of an agent, a longer washout period will be required, as agreed upon by AstraZeneca and the Inv.; 6.Major surgical procedure (as defined by the Inv.) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable; 7.Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the lab values defined in the incl. criterion *Patients with Grade ≥2 neuropathy or with irreversible toxicity not reasonably expected to be exacerbated by treatm. with MEDI4736 (eg, hearing loss) may be included after consultation with the Inv.; 8.Current or prior use of immunosuppressive medication within 14 days before the 1st dose of MEDI4736. The following are exceptions to this criterion:- Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection)- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent- Steroids as pre-medication for hypersensitivity reactions; 9.History of allogeneic organ transplantation; 10. Active or prior documented autoimmune or inflammatory disorders
    (eg, inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener syndrome [granulomatosis with polyangitis]; myasthenia gravis; Graves' disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: *Patients with vitiligo or alopecia *Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement or other chronic skin conditions not requiring systemic treatment; 11. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness or social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs from MEDI4736, or compromise the ability of the pt to give written informed consent; 12. History of another primary malignancy except for *Malignancy treated with curative intent and with no known active disease ≥5 yrs before the 1st dose of study drug and of low potential risk for recurrence *Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease *Adequately treated carcinoma in situ without evidence of disease eg cervical cancer in situ; 13. Pts with history of brain metastases, spinal cord compression, leptomeningeal carcinomatosis, or involvement of any other anatomic area that, in the opinion of the Inv., may cause significant symptoms if an inflammatory reaction occurs; 14. History of active primary immunodeficiency; 15. Known history of previous clinical diagnosis of tuberculosis; 16. Active infection incl. hep-B, hep-C, or HIV; 17. Receipt of live, attenuated vaccine within 30 days prior to the 1st dose of MEDI4736. Note: Pts should not receive live vaccine during the study and up to 30 days after the last dose of MEDI4736; 18. Female pts who are pregnant or breast-feeding or male or female pts of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of MEDI4736; 19. Known allergy or hypersensitivity to MEDI4736 or any excipient; 20. Mean QT interval corrected for heart rate ≥470 msec calculated from 3 ecg's using Fridericia's Correction; 21. Any condition that, in the opinion of the Inv., would interfere with evaluation of the IP or interpretation of pt safety or study results
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the objective response rate (ORR). ORR is defined as the number (%) of patients with a confirmed overall response of complete response (CR) or partial response (PR) and will be based on all treated patients who have measurable disease at baseline per BICR.
    E.5.1.1Timepoint(s) of evaluation of this end point
    A confirmed response of confirmed or partial response means that a response of complete or partial response is recorded at one visit and confirmed by repeat imaging not less than 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and confirmed or partial response confirmation visit. Therefore, data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of objective response rate.
    E.5.2Secondary end point(s)
    1. Duration of response (DoR) - time from the date of first documented response until the first date of documented progression or death in the absence of disease progression.
    2. Disease control rate (DCR) - percentage of patients who have a best objective response (BoR) of confirmed or partial response in the first 4 or 12 months or who have demonstrated stable disease (SD) for a minimum interval of 16 or 52 weeks following the start of treatment.
    3. Progression-free survival (PFS) - time from the date of first dose until the date of objective disease progression or death.
    4. Overall survival (OS) - time from the date of enrollment until death due to any cause.
    5. Best objective response (BoR) - the best response a patient has had during their time in the
    study up until RECIST 1.1 progression or confirmed progression or the last evaluable assessment.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. DoR - time of the initial response will be defined as the latest of the dates contributing towards the first visit response of PR or CR.
    2. DCR - first 4 or first 12 months.
    3. PFS time will be derived based on scan/assessment dates.
    4. OS - Survival calls will be made in the week following the date of data cut-off for the analysis, and if patients are confirmed to be alive or if the death date is post the data cut-off date, these patients will be censored at the date of data cut-off.
    5. BoR - for deaths occuring ≤17 weeks after enrollment BoR will be assigned to the progressive disease (PD) category and for deaths occuring >17 weeks after enrollment BoR will be assigned to the not evaluable (NE) category.
    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 Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA75
    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
    Czech Republic
    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
    Last visit of the last patient undergoing the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 67
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 112
    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)
    After the final analysis, AstraZeneca will continue to supply open-label drug to patients receiving MEDI4736 as long as, in the Investigator’s opinion, the patient is gaining clinical benefit from active treatment. Patients will only be able to restart treatment once; thus, a maximum of two 12-month treatment periods will be allowed.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-01-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-07-13
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