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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02445248




Registration number
NCT02445248
Ethics application status
Date submitted
5/05/2015
Date registered
15/05/2015

Titles & IDs
Public title
Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients
Scientific title
A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
Secondary ID [1] 0 0
2014-003060-20
Secondary ID [2] 0 0
CCTL019C2201
Universal Trial Number (UTN)
Trial acronym
JULIET
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diffuse Large B-cell Lymphoma (DLBCL) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Other - Tisagenlecleucel
Treatment: Drugs - Lymphodepleting chemotherapy

Experimental: Tisagenlecleucel - Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received tisagenlecleucel.


Treatment: Other: Tisagenlecleucel
The target dose of CTL019 transduced cells for adult patients consisted of a single infusion of 5 x 10\^8 viable CTL019 transduced cells, which was administered via intravenous infusion. The acceptable dose range was 1 - 5x10\^8 viable CTL019 transduced cells.

Treatment: Drugs: Lymphodepleting chemotherapy
Prior to CTL019 cell infusion, an additional lymphodepleting chemotherapy cycle was planned. The use of any additional bridging therapy prior to the recommended lymphodepleting chemotherapy was at the discretion of the investigator and dependent on the patient's disease burden. Lymphodepleting chemotherapy was started 14 to 5 days before CTL019 infusion (D1) to allow for at least 48 hours from last dose of lymphodepleting chemotherapy to CTL019 infusion. The lymphodepleting regimen was: Fludarabine (25 mg/m\^2 intravenously \[i.v.\] daily for 3 doses) and cyclophosphamide (250 mg/m\^2 i.v. daily for 3 doses starting with the first dose of fludarabine).
Intervention code [1] 0 0
Treatment: Other
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Main Cohort
Assessment method [1] 0 0
ORR, which includes complete response (CR) and partial response (PR) in the Main cohort as determined by IRC assessment. ORR is the percentage of participants with a best overall disease response of CR or PR, where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until progressive disease or start of new anticancer therapy (including ASCT), whichever comes first. Response was assessed according to Evaluation Criteria in diffuse large B cell lymphoma studies (based on Cheson Response criteria and the Lugano Classification (2014))
Timepoint [1] 0 0
60 months
Secondary outcome [1] 0 0
Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients
Assessment method [1] 0 0
ORR, which includes complete response (CR) and partial response (PR) in the Main cohort as determined by IRC assessment. ORR is the percentage of participants with a best overall disease response of CR or PR, where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until progressive disease or start of new anticancer therapy (including ASCT), whichever comes first.
Timepoint [1] 0 0
5 years
Secondary outcome [2] 0 0
Time to Response (TTR) as Assessed by Independent Review Committee (Main Cohort & All Patients)
Assessment method [2] 0 0
TTR is the time between date of CTL019 infusion until first documented response (CR or PR).
Timepoint [2] 0 0
up to approx. 3.3 months
Secondary outcome [3] 0 0
Duration of Overall Response (DOR) Per IRC
Assessment method [3] 0 0
DOR is the time from achievement of CR or PR, whichever occurs first, to relapse or death due to diffuse large B-cell lymphoma (DLBCL).
Timepoint [3] 0 0
up to approx. 60.1 months
Secondary outcome [4] 0 0
Event Free Survival (EFS) Per Independent Review Committee
Assessment method [4] 0 0
EFS is the time from date of CTL019 infusion to the date of first documented disease progression or relapse, new treatment for lymphoma or death due to any cause.
Timepoint [4] 0 0
up to approx. 61 months
Secondary outcome [5] 0 0
Progression Free Survival (PFS) Per Independent Review Committee
Assessment method [5] 0 0
PFS is the time from date of CTL019 infusion to the date of first documented disease progression or death due to any cause.
Timepoint [5] 0 0
up to approx. 61 months
Secondary outcome [6] 0 0
Overall Survival (OS) Per Independent Review Committee
Assessment method [6] 0 0
OS is the time from date of CTL019 infusion to the date of death due to any cause.
Timepoint [6] 0 0
60 months
Secondary outcome [7] 0 0
Pharmacokinetics (Pk): Cmax
Assessment method [7] 0 0
Cmax is the maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration. Cmax, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. The reported Cmax is the summary of maximum level observed based on the data from each patient and based on all the data that's been collected for up to 60 months in a patient.
Timepoint [7] 0 0
60 months
Secondary outcome [8] 0 0
Pharmacokinetics (Pk): Tmax
Assessment method [8] 0 0
Tmax is the time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days). Tmax, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. The time frame of 60 months refers to the duration for which the data were reviewed to identify the time of Cmax for this measure.
Timepoint [8] 0 0
60 months
Secondary outcome [9] 0 0
Pharmacokinetics (Pk): AUC0-28d and AUC0-84d
Assessment method [9] 0 0
The AUC from time zero to day 28 and 84 or other disease assessment days, in peripheral blood. AUC0-28d and AUC0-84d, based on the transgene level data by qPCR, were summarized by Month 3 response, per Independent Review Committee assessment.
Timepoint [9] 0 0
0 - 28 days after infusion for AUC0-28d, 0 - 84 days after infusion for AUC0-84d
Secondary outcome [10] 0 0
Pharmacokinetics (Pk): T1/2
Assessment method [10] 0 0
T1/2 is the half-life associated with the disposition phase slopes (alpha, beta, gamma etc.) of a semi logarithmic concentration-time curve in peripheral blood. T1/2, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. This time frame of 60 months reflects the maximum duration up to which the transgene levels were collected to measure the half life.
Timepoint [10] 0 0
60 months
Secondary outcome [11] 0 0
Pharmacokinetics (Pk): Clast
Assessment method [11] 0 0
Clast is the last observed quantifiable concentration in peripheral blood. Clast, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. This time frame reflects maximum duration of 60 months up to which the transgene levels were collected.
Timepoint [11] 0 0
60 months
Secondary outcome [12] 0 0
Pharmacokinetics (Pk): Tlast
Assessment method [12] 0 0
Tlast is the time of last observed quantifiable concentration in peripheral blood. Tlast, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. This time frame reflects maximum duration of 60 months up to which the transgene levels were collected.
Timepoint [12] 0 0
60 months
Secondary outcome [13] 0 0
Incidence of Immunogenicity to CTL019
Assessment method [13] 0 0
This is defined as the percentage of participants who tested positive for anti-mCAR19 antibodies at any time post-baseline, reported by complete response (CR), partial response (PR), Stable disease (SD), progressive disease (SD), Unknown for all participants who received with tisagenlecleucel.
Timepoint [13] 0 0
pre-infusion and at any time point post-baseline, up to duration of the study, up to 5 years

Eligibility
Key inclusion criteria
* Written informed consent must be obtained prior to any screening procedures
* Histologically confirmed DLBCL at last relapse(by central pathology review before enrolment.

.- Relapsed or refractory disease after =2 lines of chemotherapy including rituximab and anthracycline and either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT
* Measurable disease at time of enrollment
* Life expectancy =12 weeks
* Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening
* Adequate organ function:

* Renal function defined as:

* A serum creatinine of =1.5 x Upper Limit of Normal ULN OR
* Estimated Glomerular Filtration Rate (eGFR) = 60 mL/min/1.73 m^2
* Liver function defined as:

* Alanine Aminotransferase (ALT) = 5 times the Upper Limit of Normal (ULN) for age
* Bilirubin = 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is = 3.0 x ULN and direct bilirubin = 1.5 x ULN
* Must have a minimum level of pulmonary reserve defined as = Grade 1 dyspnea and pulse oxygenation > 91% on room air
* Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) = 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA)
* Adequate bone marrow reserve without transfusions defined as:

* Absolute neutrophil count (ANC) > 1.000/mm^3
* Absolute lymphocyte count (ALC) = 300/mm^3 and absolute number of CD3+ T cells > 150/mm^3
* Platelets = 50.000//mm^3
* Hemoglobin > 8.0 g/dl
* Must have an apheresis product of non-mobilized cells accepted for manufacturing
* Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following CTL019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
* Treatment with any prior gene therapy product
* Active Central Nervous System (CNS) involvement by malignancy
* Prior allogeneic HSCT
* Eligible for and consenting to HSCT
* Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
* Investigational medicinal product within the last 30 days prior to screening
* The following medications are excluded:

* Steroids: Therapeutic doses of steroids must be stopped >72 hours prior to leukapheresis and >72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: < 12 mg/m^2/day hydrocortisone or equivalent
* Immunosuppression: Any other immunosuppressive medication must be stopped =2 weeks prior to leukapheresis and = 2 weeks prior to CTL019 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators)
* Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of leukapheresis and 2 weeks prior to infusion
* Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase inhibitors, and hydroxyurea) must be stopped > 72 hour prior to leukapheresis and > 72 hours prior to CTL019 infusion
* Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to CTL019 infusion
* Fludarabine may be associated with prolonged lymphopenia. This should be taken into consideration when evaluating the optimal timing for leukapheresis collection.

* Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respected antibody, whichever is longer
* CNS disease prophylaxis must be stopped > 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate)
* Prior radiation therapy within 2 weeks of infusion
* Active replication of or prior infection with hepatitis B or active hepatitis C( HCV RNA positive )
* HIV positive patients
* Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive = 72 hours prior to infusion)
* Unstable angina and/or myocardial infarction within 6 months prior to screening
* Previous or concurrent malignancy with the following exceptions:

* Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
* In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
* A primary malignancy which has been completely resected and in complete remission for = 5 years
* Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 24 hours before lymphodepletion
* Intolerance to the excipients of the CTL019 cell product
* Cardiac arrhythmia not controlled with medical management
* Prior treatment with any adoptive T cell therapy
* Patients with T-cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly, Richter's transformation, and Burkitt lymphoma
* Patients with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis)

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
29/07/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
22/12/2022
Sample size
Target
Accrual to date
Final
115
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Melbourne
Recruitment hospital [2] 0 0
Novartis Investigative Site - Camperdown
Recruitment postcode(s) [1] 0 0
3000 - Melbourne
Recruitment postcode(s) [2] 0 0
NSW - Camperdown
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Georgia
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Kansas
Country [5] 0 0
United States of America
State/province [5] 0 0
Maryland
Country [6] 0 0
United States of America
State/province [6] 0 0
Michigan
Country [7] 0 0
United States of America
State/province [7] 0 0
Minnesota
Country [8] 0 0
United States of America
State/province [8] 0 0
New York
Country [9] 0 0
United States of America
State/province [9] 0 0
Ohio
Country [10] 0 0
United States of America
State/province [10] 0 0
Oregon
Country [11] 0 0
United States of America
State/province [11] 0 0
Pennsylvania
Country [12] 0 0
United States of America
State/province [12] 0 0
Texas
Country [13] 0 0
Austria
State/province [13] 0 0
Vienna
Country [14] 0 0
Canada
State/province [14] 0 0
Ontario
Country [15] 0 0
Canada
State/province [15] 0 0
Quebec
Country [16] 0 0
France
State/province [16] 0 0
Pierre Benite
Country [17] 0 0
Germany
State/province [17] 0 0
Nordrhein-Westfalen
Country [18] 0 0
Germany
State/province [18] 0 0
Wuerzburg
Country [19] 0 0
Italy
State/province [19] 0 0
MI
Country [20] 0 0
Japan
State/province [20] 0 0
Fukuoka
Country [21] 0 0
Japan
State/province [21] 0 0
Hokkaido
Country [22] 0 0
Japan
State/province [22] 0 0
Tokyo
Country [23] 0 0
Netherlands
State/province [23] 0 0
Amsterdam
Country [24] 0 0
Norway
State/province [24] 0 0
Oslo

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT02445248