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    Summary
    EudraCT Number:2015-005007-86
    Sponsor's Protocol Code Number:KTE-C19-101
    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:2016-05-23
    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 number2015-005007-86
    A.3Full title of the trial
    A Phase 1/2 Multi-Center Study Evaluating the Safety and Efficacy of KTE C19 in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) (ZUMA-1)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study Evaluating the Safety and Effectiveness of KTE C19 in Subjects with Aggressive Non-Hodgkin Lymphoma (NHL) resistant to other treatments.
    A.3.2Name or abbreviated title of the trial where available
    ZUMA-1
    A.4.1Sponsor's protocol code numberKTE-C19-101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02348216
    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 Address2225 Colorado Avenue
    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/CD3zeta chimeric antigen receptor.
    D.3.9.4EV Substance CodeSUB182800
    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
    Diffuse Large B-cell Lymphoma (DLBCL), Primary Mediastinal B cell lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL).
    E.1.1.1Medical condition in easily understood language
    Cancers of white blood cells, collectively known as B-cell non-Hodgkin lymphoma.
    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 HLT
    E.1.2Classification code 10036711
    E.1.2Term Primary mediastinal large B-cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10012819
    E.1.2Term Diffuse large B-cell lymphomas
    E.1.2System Organ Class 100000004851
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the phase 1 study is to evaluate the safety of axicabtagene ciloleucel regimens. The primary objective of the phase 2 pivotal study is to evaluate the efficacy of axicabtagene ciloleucel, as measured by objective response rate (ORR) in subjects with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL). The primary objective of the Phase 2 safety management study is to assess the impact of a prophylactic regimen or earlier interventions on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities.
    E.2.2Secondary objectives of the trial
    Secondary objectives of phase 2 pivotal study will include assessing the safety and tolerability of axicabtagene ciloleucel and additional efficacy endpoints. Secondary objectives of the Phase 2 safety management study include assessment of efficacy, levels of anti-CD19 chimeric antigen receptor
    (CAR) T cells, cytokines in blood/serum, and the change in European Quality of Life-5 Dimensions (EQ-5D) scores from baseline to Month 6.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    101. Histologically confirmed aggressive B cell NHL, including the following types defined by WHO 2008 (Campo et al, 2011):
    - DLBCL not otherwise specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; OR
    - primary mediastinal (thymic) large B cell lymphoma
    - transformation of follicular lymphoma to DLBCL will also be included

    102. Chemotherapy-refractory disease, defined as one or more of the following:
    - No response to first-line therapy (primary refractory disease); subjects who are intolerant to first-line therapy chemotherapy are excluded
    - PD as best response to first-line therapy
    - SD as best response after at least 4 cycles of first-line therapy (e.g., 4 cycles of R-CHOP) with SD duration no longer than 6 months from last dose of therapy
    OR
    - No response to second or greater lines of therapy
    - PD as best response to most recent therapy regimen
    - SD as best response after at least 2 cycles of last line of therapy with SD duration no longer than 6 months from last dose of therapy
    OR
    - Refractory post-ASCT
    - Disease progression or relapsed ≤12 months of ASCT (must have biopsy proven recurrence in relapsed subjects)
    - if salvage therapy is given post-ASCT, the subject must have had no response to or relapsed after the last line of therapy

    103. Subjects must have received adequate prior therapy including at a minimum:
    - anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 negative, and
    - an anthracycline containing chemotherapy regimen;
    - for subjects with transformed FL must have received prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to DLBCL

    104. At least 1 measurable lesion according to the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy

    105. MRI of the brain showing no evidence of CNS lymphoma

    106. At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy. At least 3 half-lives must have elapsed from any prior systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists etc).

    107. Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for clinically non-significant toxicities such as alopecia)

    108. Age 18 or older

    109. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

    110. ANC ≥1000/uL

    111. Platelet count ≥75,000/uL

    112. Absolute lymphocyte count ≥100/uL

    113. Adequate renal, hepatic, pulmonary and cardiac function defined as:
    - Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min
    - Serum ALT/AST ≤2.5 ULN
    - Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert’s syndrome.
    - Cardiac ejection fraction ≥ 50% ,no evidence of pericardial effusion as determined by an ECHO, and no clinically significant ECG findings
    - No clinically significant pleural effusion
    - Baseline oxygen saturation >92% on room air

    114. 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)

    Additional criteria specific for Phase 2 safety management study:
    115. Relapsed or refractory large B-cell lymphoma including DLBCL, PMBCL, TFL, and HGBCL after two systemic lines of therapy
    E.4Principal exclusion criteria
    201. History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years

    202. History of Richter’s transformation of CLL

    203. Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel infusion

    204. History of allogeneic stem cell transplantation

    205. Prior CD19 targeted therapy with the exception of subjects who received axicabtagene ciloleucel in this study and are eligible for re-treatment

    206. Prior chimeric antigen receptor therapy or other genetically modified T cell therapy

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

    208. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management.

    209. History of HIV infection or acute or chronic active hepatitis B or C infection. Subjects with history of hepatitis infection must have cleared their infection as determined by standard serological and genetic testing per current Infectious Diseases Society of America (IDSA) guidelines.

    210. Presence of any indwelling line or drain (e.g., 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

    211. Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of CNS lymphoma or primary CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases

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

    213. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement

    214. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment

    215. Expected or possible requirement for urgent therapy within 6 weeks due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome)

    216. Primary immunodeficiency

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

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

    219. History of severe immediate hypersensitivity reaction to any of the agents used in this study

    220. Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen

    221. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential

    222. Subjects of both genders who are not willing to practice birth control from the time of consent through 6 months after the completion of axicabtagene ciloleucel

    223. In the investigator's 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

    224. History of autoimmune disease (e.g. Crohn's, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1 Study: Incidence of adverse events defined as dose-limiting toxicities (DLT)
    Phase 2 Pivotal Study: Objective response rate (complete response [CR] + partial response [PR]) per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma as determined by study investigators. All subjects who do not meet the criteria for an objective response by the analysis cutoff date will be considered non-responders.
    Phase 2 Safety Management Study: Assess the rate and severity of CRS and neurologic toxicities.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1 Study: The primary analysis of Cohort 1 will occur after 72 subjects in the mITT set have had the opportunity to be assessed for response 6 months after the axicabtagene ciloleucel infusion.
    Phase 2 Pivotal Study: The primary analysis of Cohorts 1 and 2 combined will be performed when 72 subjects in the mITT set of Cohort 1 and 20
    subjects in the mITT set of Cohort 2 have had the opportunity to be evaluated for response at 6 months after the target axicabtagene ciloleucel infusion.
    Phase 2 Safety Management Study: The primary analysis of Cohort 3 and Cohort 4 will occur after all treated subjects in each cohort have had the opportunity to be followed for 6 months, respectively.
    E.5.2Secondary end point(s)
    Phase 1 study:
    • Objective response rate (CR + PR) per the revised IWG Response Criteria for Malignant Lymphoma
    • Duration of Response (DOR)
    • Overall Survival (OS)
    • Progression Free Survival (PFS)
    • Incidence of adverse events and clinical significant changes in safety lab values
    • Levels of anti-CD19 CAR T cells in blood
    • Levels of cytokines in serum
    • Incidence of anti-axicabtagene ciloleucel antibodies

    Phase 2 Pivotal Study:
    • Objective response rate per Independent Radiology Review Committee (IRRC)
    • DOR
    • PFS
    • OS
    • Incidence of adverse events and clinical significant changes in safety lab values
    • Levels of anti-CD19 CAR T cells in blood
    • Levels of cytokines in serum
    • Incidence of anti-axicabtagene ciloleucel antibodies

    Phase 2 Safety Management Study:
    • Objective response rate (complete response [CR] + partial response [PR]) per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma (Cheson et al, 2007) as determined by study investigators.
    • DOR
    • PFS
    • OS
    • Incidence of adverse events and clinically significant changes in safety lab values
    • Levels of anti-CD19 CAR T cells in blood
    • Levels of cytokines in blood
    • Incidence of anti-axicabtagene ciloleucel antibodies
    • Changes over time in the EQ-5D scale score and visual analogue scale (VAS) score (Phase 2 SMS only)
    E.5.2.1Timepoint(s) of evaluation of this end point
    All enrolled subjects will be followed in the long term follow-up period for survival and disease status, if applicable. Subjects will begin the long term follow-up period after they have completed the Month 3 visit of the post treatment assessment period (whether they have responded to treatment or went straight to the month 3 visit due to disease progression)
    • Every 3 months (± 2 weeks) through Month 18
    • Every 6 months (± 1 month) between Month 24 - Month 60
    • Beginning with year 6, Month 72 (± 3 months), subjects will return to the clinic 1 time annually up to 15 years.
    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) 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 I to assess safety, Phase II to assess efficacy of KTE-C19 and safety management study
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    Canada
    France
    Germany
    Israel
    Netherlands
    United States
    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: 196
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 196
    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 Decision2017-07-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-04-03
    P. End of Trial
    P.End of Trial StatusOngoing
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