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    Summary
    EudraCT Number:2018-003118-42
    Sponsor's Protocol Code Number:D419EC00001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-02-18
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-003118-42
    A.3Full title of the trial
    Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of Durvalumab Monotherapy or Durvalumab in Combination with Tremelimumab in Pediatric Patients with Advanced Solid Tumors and Hematological Malignancies
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study to evaluate the safety, tolerability and early efficacy of the study drug (Durvalumab) alone and a combination of study drugs (Durvalumab and Tremelimumab) in children with advance solid tumours and blood cancer
    A.4.1Sponsor's protocol code numberD419EC00001
    A.5.4Other Identifiers
    Name:INDNumber:141756
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/081/2018
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca AB
    B.5.2Functional name of contact pointInformation Centre
    B.5.3 Address:
    B.5.3.1Street AddressN/A
    B.5.3.2Town/ citySödertälje
    B.5.3.3Post code151 85
    B.5.3.4CountrySweden
    B.5.6E-mailinformation.centre@astrazeneca.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 nameDurvalumab
    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 INNDURVALUMAB
    D.3.9.1CAS number 1428935-60-7
    D.3.9.2Current sponsor codeMEDI4736
    D.3.9.3Other descriptive nameDURVALUMAB
    D.3.9.4EV Substance CodeSUB176342
    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.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 nameTremelimumab
    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 INNTREMELIMUMAB
    D.3.9.1CAS number 745013-59-6
    D.3.9.3Other descriptive nameTREMELIMUMAB
    D.3.9.4EV Substance CodeSUB37101
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Advanced Solid Tumors and Hematological Malignancies
    E.1.1.1Medical condition in easily understood language
    solid tumours or blood cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065143
    E.1.2Term Malignant solid tumour
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10066481
    E.1.2Term Hematological malignancy
    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
    Dose-finding:
    -To determine the adult equivalent exposure/MTD/recommended Phase II pediatric dose of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy.

    -To determine the safety profile of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy

    Dose-expansion:
    To determine the preliminary antitumor activity of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy at the recommended dose, using cohortspecific response criteria (eg, Cheson criteria and RECIST 1.1).
    E.2.2Secondary objectives of the trial
    Dose-finding and dose-expansion:

    -To describe the PK of durvalumab and tremelimumab in combination and durvalumab as monotherapy following combination therapy, in children and young adults with solid tumors, or hematological malignancies

    -To determine the immunogenicity of durvalumab and tremelimumab in combination and durvalumab as monotherapy following combination therapy, in children and young adults with solid tumors

    -To determine the immunogenicity of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, in children and young adults with hematological malignancies

    -To measure effects on immune checkpoint inhibition in response to routine immunizations (dose-expansion phase only).

    -To evaluate immune activation and counts of NK-, B- and T-cells
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients must have pathologically confirmed relapsed or refractory advanced solid tumour malignancy or haematological malignancies including lymphoma and acute leukaemia. Any number of prior treatment regimens allowed. A select group of first-line patients may be eligible for screening and enrolment. These patients will be enrolled based on investigator assessment as patients for whom no curative standard of care treatment options exist or such therapies are not tolerable.

    • If available, patients must provide a diagnostic tumor sample taken ˂3 years prior to screening for evaluation of PD-L1 status.

    • Lansky play performance scale ≥50 for patients ≥1 and <16 years of age and Karnofsky performance status score ≥50 for patients ≥16 years of age (patients <1 year of age are exempt from this criterion)

    • Patients must have measurable/evaluable disease as defined by methods used in common clinical practice.

    • No prior exposure to immune checkpoint inhibitors or genetically engineered cellular therapies including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies and antibodies of CAR-T or other cell therapies, excluding therapeutic anticancer vaccines. Exposure to other investigational agents may be permitted after discussion with the Sponsor or designee.
    E.4Principal exclusion criteria
    • History of allogeneic organ transplantation (exceptions may be allowed for HL, NHL, ALL and AML, after discussion with Sponsor or designee). Patients who have previously received an autologous bone marrow transplant may be eligible

    • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis, celiac disease or other serious GI chronic conditions associated with diarrhea, systemic lupus erythematosus, Wegener syndrome; myasthenia gravis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc) autoimmune myocarditis, and autoimmune pneumonitis. The following are exceptions to this criterion:
    − Patients with vitiligo or alopecia
    − Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
    − Psoriasis that does not require systemic therapy
    − Patients with celiac disease controlled by diet alone.

    • Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, cardiac arrhythmia, ILD, or psychiatric illness or social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs from IP, or compromise the ability of the patient to give written informed consent.

    • History of primary immunodeficiency.

    • Active infection including tuberculosis, hepatitis B, hepatitis C, or HIV. Patients with a past or resolved HBV infection are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).

    • Any unresolved toxicity NCI CTCAE version 5.0 Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, lymphopenia and the laboratory values defined in the inclusion criteria
    − Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician.
    − Patients with toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab (eg, hearing loss, gastrostomy tube) may be included after consultation with the Study Physician.

    • Patients with clinically active brain metastases (known or suspected) or spinal cord compression, and choloromas are excluded, unless these conditions have been previously treated and are considered stable.

    • History of leptomeningeal carcinomatosis, or involvement of any other anatomic area that, in the opinion of the Investigator, may cause significant symptoms if an inflammatory reaction occurs.
    E.5 End points
    E.5.1Primary end point(s)
    Dose-finding:
    1. Based on PK parameters (including Cmax, Cmin, AUC, and others), identify the adult equivalent
    exposure/MTD of durvalumab monotherapy and durvalumab in combination with tremelimumab
    among children and young adults from birth to <18 years of age with advanced solid tumors and non-Hodgkin lymphoma, using a q4w dosing schedule.
    2. Identify the safety and tolerability of durvalumab monotherapy and durvalumab in combination with tremelimumab at the adult equivalent exposure/MTD among children and young adults from birth to <18 years of age with advanced solid tumors and non-Hodgkin lymphoma, using a q4w
    dosing schedule. Endpoints include AEs, vital signs, physical examinations, ECGs, and
    laboratory evaluations.

    Dose-expansion:
    3. Objective response rate as determined by the Investigator assessed RECIST 1.1 or alternative
    pre-specified tumor-specific response rates for different scoring systems.
    -Assessment of antitumor activity will be specific to tumor cohort, eg, Investigator assessed RECIST 1.1 and Cheson criteria (other malignancies will be analyzed based on the best response assessed by the Investigator).
    4. Additional efficacy endpoints that will be collected include DoR, BoR, DCR, PFS, APF12,
    and APF18 based on RECIST 1.1, Cheson criteria, Wayne criteria, or INRC assessed by the
    Investigator, and OS, OS12, and OS24 as appropriate to each individual cohort.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. From first dose to cycle 12 on dosing days

    2. From baseline to 90 days post-treatment discontinuation (for AEs)

    3. From baseline to progression

    4. From baseline to death/data cut-off for analysis (survival)
    E.5.2Secondary end point(s)
    5. Individual durvalumab and tremelimumab concentrations in serum, and PK parameters
    including Cmax, Cmin, AUC.

    6. Number and percentage of patients who develop detectable ADAs.

    7. Individual antibody titer measurements before and after planned routine immunization during
    treatment and Cycle 4 or follow-up, whichever is earlier.

    8. Flow cytometry for CD4, CD8, B and NK cells, including T-cell activation with Ki67
    E.5.2.1Timepoint(s) of evaluation of this end point
    5. From first dose to cycle 12 on dosing days

    6 & 7. Pre- first dose and pre-dose cycle 6 (durvalumab) and cycle 4 (tremelimumab)

    8. From first dose to cycle 2
    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 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
    Dose-finding & Dose-expansion
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    United States
    France
    Germany
    Italy
    Netherlands
    Spain
    United Kingdom
    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 is defined as 'the 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 years5
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 228
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 3
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 34
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 80
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 111
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children from birth until 18 years old
    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 155
    F.4.2.2In the whole clinical trial 228
    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 durvalumab monotherapy or durvalumab + tremelimumab combination therapy up to
    the time that they discontinue the treatment for whatever reason
    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 Decision2019-02-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-09-17
    P. End of Trial
    P.End of Trial StatusOngoing
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