Clinical Trials Register

Summary
EudraCT Number:	2019-002291-13
Sponsor's Protocol Code Number:	KTE-C19-112
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-09-10
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

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2019-002291-13

A.3

Full title of the trial

A Phase 2 Multicenter Study Evaluating the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Subjects with High-Risk Large B-Cell Lymphoma (ZUMA-12)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study evaluating the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Subjects with High-Risk Large B-Cell Lymphoma

A.4.1

Sponsor's protocol code number

KTE-C19-112

A.5.4

Other Identifiers

Name:

IND number

Number:

016273

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Kite Pharma, Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Kite Pharma, Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Kite Pharma, Inc
B.5.2	Functional name of contact point	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	2400 Broadway
B.5.3.2	Town/ city	Santa Monica
B.5.3.3	Post code	CA 90404
B.5.3.4	Country	United States
B.5.6	E-mail	regulatory@kitepharma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Yescarta
D.2.1.1.2	Name of the Marketing Authorisation holder	Kite Pharma EU B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1393
D.3 Description of the IMP
D.3.1	Product name	axicabtagene ciloleucel
D.3.2	Product code	axicabtagene ciloleucel
D.3.4	Pharmaceutical form	Dispersion for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	axicabtagene ciloleucel
D.3.9.2	Current sponsor code	KTE-C19
D.3.9.3	Other descriptive name	axicabtagene ciloleucel
D.3.9.4	EV Substance Code	SUB188282
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	200000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Yes
D.3.11.3.5.1	CAT classification and reference number	Gene therapy medicinal product. Doc. Ref. EMA/CAT/360525/2015
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	Yes
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Adult subjects with high-risk large B-cell lymphoma, including either high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 translocations (double-hit or triple-hit lymphomas) or International Prognostic Index (IPI) score ≥3.

E.1.1.1

Medical condition in easily understood language

Cancers of white blood cells

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10012819
E.1.2	Term	Diffuse large B-cell lymphomas
E.1.2	System Organ Class	100000004851

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To estimate the efficacy of axicabtagene ciloleucel, as measured by CR rate, in subjects with high-risk large B-cell lymphoma, as determined by study investigators

E.2.2

Secondary objectives of the trial

To characterize the safety profile, and to further characterize efficacy with secondary endpoints; further secondary objectives will include pharmacokinetic/pharmacodynamic endpoints.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

101. Histologically confirmed large B-cell lymphoma, including the following types defined by WHO 2016 (Swerdlow et al, 2016):
 - Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), including Germinal center B-cell (GCB) type and activated B-cell (ABC) type; Intravascular large B-cell lymphoma; T-cell/histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV + DLBCL, NOS;
 - High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit)
 - High-grade B-cell lymphoma, NOS

102. High risk large B-cell lymphoma, defined as one or more of the following:
 High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 translocations (double-hit or triple-hit) as determined by investigator by fluorescent in situ hybridization (FISH)
OR
 International Prognostic Index (IPI) score of ≥3 at initial diagnosis or anytime between initial diagnosis and enrolment

103. Subjects must have a positive interim PET per Cheson, 2014 (Deauville PET score of 4 or 5) after 2 cycles (PET2+) of chemoimmunotherapy as follows:
 2 cycles of a dose intense anti-CD20 monoclonal antibody and anthracycline containing regimen (e.g. DA-EPOCH-R) x 2 cycles with or without intrathecal chemotherapy at the discretion of the investigator per standard of care for double-hit or triple-hit lymphoma
OR
 2 cycles of a standard anti-CD20 monoclonal antibody and anthracycline containing regimen (e.g. R-CHOP) for large B-cell lymphoma with IPI score of ≥3

104. At least 2 weeks must have elapsed since any prior systemic therapy at the time the subject is planned for leukapheresis

105. No evidence, suspicion and/or history of CNS involvement of lymphoma

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

107. Age 18 or older

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

109. ANC ≥ 1000/μL

110. Platelet count ≥ 75,000/μL

111. Absolute lymphocyte count ≥ 100/μL

112. Adequate renal, hepatic, pulmonary, and cardiac function defined as:
a. Creatinine clearance (as estimated by Cockcroft Gault) ≥ 60 mL/min
b. Serum ALT/AST ≤2.5 ULN
c. Total bilirubin ≤1.5 mg/dL, except in subjects with Gilbert’s syndrome

113. Cardiac ejection fraction ≥ 50% , no evidence of pericardial effusion as determined by an ECHO, and no clinically significant ECG findings

114. No clinically significant pleural effusion

115. Baseline oxygen saturation > 92% on room air

116. 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.4

Principal 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. Prior CD19-targeted therapy

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

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

207. Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management; simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if responding to active treatment and after consultation with the sponsor’s medical monitor

208. 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 or applicable country guidelines

209. 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

210. Subjects with detectable cerebrospinal fluid malignant cells, brain metastases, or active CNS lymphoma

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

212. Subjects with cardiac atrial or cardiac ventricular lymphoma involvement

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

214. Requirement for urgent therapy due to tumor mass effects (eg, blood vessel compression, bowel obstruction, or transmural gastric involvement)

215. Primary immunodeficiency

216. History of autoimmune disease (eg, Crohns, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years

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 childbearing 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 conditioning chemotherapy

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

E.5 End points

E.5.1

Primary end point(s)

Complete Response (CR) rate: CR rate is defined as the incidence of a CR per the Lugano Classification (Cheson et al, 2014), as determined by study investigators. All evaluable subjects who do not meet the criteria for a CR by the analysis data cutoff date will be considered non-responders.

E.5.1.1

Timepoint(s) of evaluation of this end point

The visit schedule for disease assessments is calculated from axicabtagene ciloleucel infusion on Day 0, including CT scans, positron emission tomography (PET) scans, bone marrow biopsy, assessment of B-symptoms, physical exams needed to assess disease, and collection of subsequent anti-cancer therapy. The schedule for disease assessments is described in Table 3 of the protocol and includes assessments at Day 1-7, Week 2 and 4, and Month 2 and 3. Long-term follow up assessments are carried out every 3 months from Month 6-18, every 6 months from Month 18-60, and yearly thereafter.

E.5.2

Secondary end point(s)

- Objective response rate (ORR): ORR is defined as the incidence of either a CR or a partial response (PR) per the Lugano Classification (Cheson et al, 2014) as determined by study investigators

- Duration of response (DOR)

- Event-free survival (EFS)

- Progression-free survival (PFS)

- Overall survival (OS)

- Incidence of adverse events and clinical significant changes in safety lab values

- Relapse with central nervous system (CNS) disease

E.5.2.1

Timepoint(s) of evaluation of this end point

The schedule for disease assessments is described in Table 3 of the protocol and includes assessments at Day 1-7, Week 2 and 4, and Month 2 and 3. Long-term follow up assessments are carried out every 3 months from Month 6-18, every 6 months from Month 18-60, and yearly thereafter.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

France

United States

E.8.7

Trial 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

End of Long term follow up phase

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-12-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-02-07

P. End of Trial
P.	End of Trial Status	Ongoing

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