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Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients (JULIET)

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ClinicalTrials.gov Identifier: NCT02445248
Recruitment Status : Completed
First Posted : May 15, 2015
Results First Posted : April 18, 2024
Last Update Posted : April 18, 2024
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE May 5, 2015
First Posted Date  ICMJE May 15, 2015
Results First Submitted Date  ICMJE December 16, 2023
Results First Posted Date  ICMJE April 18, 2024
Last Update Posted Date April 18, 2024
Actual Study Start Date  ICMJE July 29, 2015
Actual Primary Completion Date December 22, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 22, 2024)		 Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Main Cohort [ Time Frame: 60 months ]
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))
Original Primary Outcome Measures  ICMJE
 (submitted: May 14, 2015)		 Overall Response Rate(ORR) [ Time Frame: 5 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 22, 2024)
  • Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients [ Time Frame: 5 years ]
    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.
  • Time to Response (TTR) as Assessed by Independent Review Committee (Main Cohort & All Patients) [ Time Frame: up to approx. 3.3 months ]
    TTR is the time between date of CTL019 infusion until first documented response (CR or PR).
  • Duration of Overall Response (DOR) Per IRC [ Time Frame: up to approx. 60.1 months ]
    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).
  • Event Free Survival (EFS) Per Independent Review Committee [ Time Frame: up to approx. 61 months ]
    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.
  • Progression Free Survival (PFS) Per Independent Review Committee [ Time Frame: up to approx. 61 months ]
    PFS is the time from date of CTL019 infusion to the date of first documented disease progression or death due to any cause.
  • Overall Survival (OS) Per Independent Review Committee [ Time Frame: 60 months ]
    OS is the time from date of CTL019 infusion to the date of death due to any cause.
  • Pharmacokinetics (Pk): Cmax [ Time Frame: 60 months ]
    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.
  • Pharmacokinetics (Pk): Tmax [ Time Frame: 60 months ]
    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.
  • Pharmacokinetics (Pk): AUC0-28d and AUC0-84d [ Time Frame: 0 - 28 days after infusion for AUC0-28d, 0 - 84 days after infusion for AUC0-84d ]
    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.
  • Pharmacokinetics (Pk): T1/2 [ Time Frame: 60 months ]
    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.
  • Pharmacokinetics (Pk): Clast [ Time Frame: 60 months ]
    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.
  • Pharmacokinetics (Pk): Tlast [ Time Frame: 60 months ]
    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.
  • Incidence of Immunogenicity to CTL019 [ Time Frame: pre-infusion and at any time point post-baseline, up to duration of the study, up to 5 years ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 14, 2015)
  • Number of participants with adverse evensts (AEs) [ Time Frame: 5 years ]
  • Number of participants with serious adverse evensts (SAEs) [ Time Frame: 5 years ]
  • Time to response (TTR) [ Time Frame: 5 years ]
  • Duration of overall response (DOR) [ Time Frame: 5 years ]
  • Event free survival (EFS) [ Time Frame: 5 years ]
  • Progression free survival (PFS) [ Time Frame: 5 years ]
  • Overall survival (OS) [ Time Frame: 5 years ]
  • ORR, PFS, OS, EFS, DOR and AEs in histological and molecular subtypes [ Time Frame: 5 years ]
  • Characterize the in vivo cellular PK profile (levels, persistence, trafficking) of CTL019 transduced cells into target tissues (blood, bone marrow, cerebral spinal fluid (CSF) and other tissues if available) [ Time Frame: 5 years ]
  • Prevalence and Incidence of immunogenicity to CTL019 [ Time Frame: 5 years ]
  • RCL by VSV-g q-PCR [ Time Frame: 5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients
Official Title  ICMJE 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)
Brief Summary This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.
Detailed Description

This was a single arm, open-label, multi-center, Phase II study conducted to determine the efficacy and safety of tisagenlecleucel in adult patients with r/r DLBCL. The study consisted of the following sequential periods: Screening, Pre-Treatment, Treatment and Primary follow-up, Secondary follow-up, Survival follow-up.

Patients were enrolled in 2 cohorts to receive one tisagenlecleucel infusion as follows:

  • Main Cohort (patients treated with tisagenlecleucel manufactured at the Novartis manufacturing facility in Morris Plains, US, referred to as "US manufacturing facility") and
  • Cohort A (patients treated with tisagenlecleucel manufactured at the Fraunhofer Institut für Zelltherapie, Leipzig, Germany, referred to as "EU manufacturing facility").

The study enrolled adult patients ≥ 18 years with histologically confirmed relapsed or refractory (r/r) DLBCL after ≥ 2 lines of chemotherapy, with a life expectancy of ≥ 12 weeks and not eligible or not consenting to stem cell transplantation (SCT).

Patients had measurable disease at time of enrollment, adequate organ function and zero or one Eastern Cooperative Oncology Group performance status at screening. For each patient, the apheresis product of non-mobilized cells was received and accepted by the manufacturing site.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Diffuse Large B-cell Lymphoma (DLBCL)
Intervention  ICMJE
  • Biological: 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.
    Other Name: CTL019
  • Drug: 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).
Study Arms  ICMJE Experimental: Tisagenlecleucel
Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received tisagenlecleucel.
Interventions:
  • Biological: Tisagenlecleucel
  • Drug: Lymphodepleting chemotherapy
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 9, 2020)		 115
Original Estimated Enrollment  ICMJE
 (submitted: May 14, 2015)		 100
Actual Study Completion Date  ICMJE December 22, 2022
Actual Primary Completion Date December 22, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Canada,   France,   Germany,   Italy,   Japan,   Netherlands,   Norway,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02445248
Other Study ID Numbers  ICMJE CCTL019C2201
2014-003060-20 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
URL: https://www.clinicalstudydatarequest.com
Current Responsible Party Novartis ( Novartis Pharmaceuticals )
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Novartis Pharmaceuticals
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date March 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP