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    Summary
    EudraCT Number:2017-002261-22
    Sponsor's Protocol Code Number:KTE-C19-107
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-01-22
    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 ConcernedGermany - PEI
    A.2EudraCT number2017-002261-22
    A.3Full title of the trial
    A Phase 3, Randomized, Open-Label Study Evaluating the Efficacy of Axicabtagene Ciloleucel versus Standard of Care Therapy in Subjects with Relapsed/Refractory Diffuse Large B Cell Lymphoma (ZUMA-7)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study Evaluating the Effectiveness of Axicabtagene Ciloleucel versus Standard of Care Therapy in Subjects with Diffuse Large B Cell Lymphoma returning after, or resistant to, initial treatment.
    A.3.2Name or abbreviated title of the trial where available
    ZUMA-7
    A.4.1Sponsor's protocol code numberKTE-C19-107
    A.5.4Other Identifiers
    Name:IND NumberNumber:016278
    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 SponsorKite Pharma, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportKite Pharma, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKite Pharma, Inc.
    B.5.2Functional name of contact pointRegulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address2400 Broadway
    B.5.3.2Town/ citySanta Monica
    B.5.3.3Post codeCA 90404
    B.5.3.4CountryUnited States
    B.5.6E-mailregulatory@kitepharma.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 Yes
    D.2.1.1.1Trade name Yescarta
    D.2.1.1.2Name of the Marketing Authorisation holderKite Pharma EU B.V.
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1393
    D.3 Description of the IMP
    D.3.1Product nameaxicabtagene ciloleucel
    D.3.2Product code axicabtagene ciloleucel
    D.3.4Pharmaceutical form Dispersion 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 INNaxicabtagene ciloleucel
    D.3.9.2Current sponsor codeKTE-C19
    D.3.9.3Other descriptive nameAutologous T cells transduced with retroviral vector encoding an anti-CD19 CD28/CD3-zeta chimeric antigen receptor.
    D.3.9.4EV Substance CodeSUB188282
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number200000000
    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) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    D.3.11.3.5.1CAT classification and reference numberGene therapy medicinal product. Doc. Ref. EMA/CAT/360525/2015
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    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
    Relapsed/Refractory Diffuse Large B cell Lymphoma (r/r DLBCL).
    E.1.1.1Medical condition in easily understood language
    Cancers of white blood cells
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10012822
    E.1.2Term Diffuse large B-cell lymphoma refractory
    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 determine if axicabtagene ciloleucel is superior to SOC as measured by event-free survival (EFS), as determined by blinded central review
    E.2.2Secondary objectives of the trial
    - To evaluate the effect of axicabtagene ciloleucel compared to SOC on objective response rate (ORR), as determined by blinded central review

    - To evaluate the effect of axicabtagene ciloleucel compared to SOC on overall survival (OS)

    - To evaluate the effect of axicabtagene ciloleucel compared to SOC on progression-free survival (PFS)

    - To evaluate the effect of axicabtagene ciloleucel compared to SOC on duration of response (DOR) and duration of complete response among responding subjects as determined by blinded central review

    - To evaluate the safety of axicabtagene ciloleucel compared to SOC

    - To evaluate the effect of axicabtagene ciloleucel on patient reported outcomes (PROs) and quality of life (QoL) compared to SOC
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    101. Histologically proven large B-cell lymphoma including the following
    types defined by WHO 2016 (Swerdlow et al, 2016)
    o DLBCL not otherwise specified (including ABC/GCB)
    o HGBL with or without MYC and BCL2 and/or BCL6 rearrangement
    o DLBCL arising from FL
    o T-cell/histiocyte rich large B-cell lymphoma
    o DLBCL associated with chronic inflammation
    o Primary cutaneous DLBCL, leg type
    o Epstein-Barr virus (EBV) + DLBCL

    102. Relapsed or refractory disease after first-line chemoimmunotherapy
    o Refractory disease defined as no complete remission to first-line
    therapy; subjects who are intolerant to first-line therapy are excluded
     Progressive disease (PD) as best response to first-line therapy
     Stable disease (SD) as best response after at least 4 cycles of first-line
    therapy (eg, 4 cycles of R-CHOP)
     Partial response (PR) as best response after at least 6 cycles, and
    biopsy-proven residual disease or disease progression ≤ 12 months of
    therapy
    o Relapsed disease defined as complete remission to first-line therapy
    followed by biopsy-proven disease relapse ≤ 12 months of first-line
    therapy

    103. Subjects must have received adequate first-line therapy including at a minimum:
    o Anti-CD20 monoclonal antibody unless investigator
    determines that tumor is CD20 negative, and
    o An anthracycline containing chemotherapy regimen

    104. Intent to proceed to HDT and ASCT if response to second-line therapy

    105. Subjects must have radiographically documented disease

    106. No known history or suspicion of central nervous system (CNS) involvement by lymphoma

    107. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic cancer therapy at the time the subject provides consent

    108. Age 18 years or older at the time of informed consent

    109. ECOG performance status of 0 or 1

    110. Adequate bone marrow, renal, hepatic, pulmonary and cardiac function defined as:
    o Absolute neutrophil count (ANC) ≥1000/µL
    o Platelet count ≥ 75,000/µL
    o Absolute lymphocyte count ≥ 100/µL
    o Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60
    mL/min
    o Serum alanine aminotransferase/aspartate aminotransferase
    (ALT/AST) ≤ 2.5 upper limit of normal (ULN)
    o Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert’s
    syndrome
    o Cardiac ejection fraction ≥ 50%, no evidence of pericardial
    effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings
    o No clinically significant pleural effusion
    o Baseline oxygen saturation > 92% on room air

    111. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential)
    E.4Principal exclusion criteria
    201. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (eg cervix, bladder, breast) unless disease free for at least 3 years

    202. History of Richter’s transformation of CLL or PMBCL

    203. History of autologous or allogeneic stem cell transplant

    204. Received more than one line of therapy for DLBCL

    205. Prior CD19 targeted therapy

    206. Treatment with systemic immunostimulatory agents (including but not limited to interferon and IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to the first dose of axicabtagene ciloleucel or SOC

    207. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy, or prior randomization into ZUMA-7

    208. History of severe, immediate hypersensitivity reaction attributed to aminoglycosides

    209. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.

    210. Known history of infection with human immunodeficiency virus (HIV) or hepatitis B (HBsAg positive) or hepatitis C virus (anti-HCV positive). If there is a positive history of treated hepatitis B or hepatitis C, the viral load must be undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.

    211. Active tuberculosis

    212. Presence of any indwelling line or drain (eg, percutaneous nephrostomy tube, indwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). Dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted.

    213. Subjects with detectable cerebrospinal fluid malignant cells or known brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases

    214. History or presence of non-malignant CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement

    215. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement

    216. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York Heart Association Class II or greater congestive heart failure, or other clinically significant cardiac disease within 12 months of enrollment

    217. Requirement for urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression

    218. History of autoimmune disease, requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years.

    219. History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.

    220. History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment

    221. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment

    222. History of severe immediate hypersensitivity reaction to tocilizumab or any of the agents used in this study

    223. Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study

    224. Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of chemotherapy on the fetus or infant. Subjects of either sex who are not willing to practice birth control from the time of consent and at least 6 months after the last dose of axicabtagene ciloleucel or SOC chemotherapy

    225. In the investigators judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation
    E.5 End points
    E.5.1Primary end point(s)
    Event Free Survival (EFS): EFS is defined as the time from randomization to the earliest date of disease progression per the Lugano Classification, commencement of new lymphoma therapy, or death from any cause. Subjects not meeting the criteria for these events by the analysis data cutoff date will be censored. For the primary analysis of EFS, disease progression events and censoring times will be determined by blinded central review. Events of new therapy and death will be based on the clinical trial database.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis of EFS will be conducted when all subjects have had the opportunity to be followed to the Month 9 disease assessment, and approximately 250 EFS events have been observed. The acceptable lower limit for the observed total EFS events is 225, which is to maintain the power for the primary analysis of EFS to within 5% of the targeted 90%. If more than 250 EFS events are observed at the time of the data cutoff for the primary analysis, all observed events will be used in the
    analysis.
    E.5.2Secondary end point(s)
    Key secondary endpoints (in order of hierarchical testing)
    • Objective response rate
    • Overall survival

    Secondary endpoints
    • EFS based on investigator disease assessments
    • Modified EFS based on blinded central review and on investigator disease assessments
    • Progression-free survival
    • Duration of response and complete response
    • Incidence of adverse events and clinically significant changes in safety lab values including antibodies to axicabtagene ciloleucel
    • Changes from screening to post baseline in the global health status QoL scale and the physical functioning domain of the EORTC QLQ-C30
    • Changes from screening to post baseline in the EQ-5D-5L index and VAS scores
    E.5.2.1Timepoint(s) of evaluation of this end point
    ORR is defined as the incidence of either a complete response or a partial response by the Lugano Classification as determined by blinded central review.
    Modified EFS is defined the same way as EFS, except that failure to attain CR or PR by Day 150 assessment is not considered as an event. OS
    is defined as the time from randomization to death from any cause. Subjects who have not died by the analysis data cutoff date will have survival time censored at their last date known to be alive. For subjects alive or dead after the data cutoff date, survival time will be censored at
    the data cutoff date.
    EFS, PFS, DOR timepoints of evaluation can be found in section 10.2.3. of the protocol.
    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 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) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA36
    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
    Canada
    Israel
    United States
    Switzerland
    Austria
    Belgium
    France
    Germany
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Defined as when the last subject is assessed or received an intervention for evaluation in the study, including survival assessments
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years15
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years15
    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: 87
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 263
    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 state48
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 175
    F.4.2.2In the whole clinical trial 350
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-08-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-20
    P. End of Trial
    P.End of Trial StatusOngoing
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