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

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)

This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.

Study Overview

• Status: Completed
• Conditions: Diffuse Large B-cell Lymphoma (DLBCL)
• Intervention / Treatment: Biological: Tisagenlecleucel; Drug: Lymphodepleting chemotherapy

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: Interventional
• Enrollment (Actual): 115
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • Camperdown, Australia, NSW
    • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
• Austria
  • Vienna, Austria, A 1090
    • Novartis Investigative Site
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Novartis Investigative Site
• France
  • Pierre Benite, France, 69495
    • Novartis Investigative Site
• Germany
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
  • Nordrhein-Westfalen
    • Koeln, Nordrhein-Westfalen, Germany, 50937
      • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
• Japan
  • Fukuoka
    • Fukuoka city, Fukuoka, Japan, 812-8582
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo city, Hokkaido, Japan, 060 8648
      • Novartis Investigative Site
  • Tokyo
    • Chuo ku, Tokyo, Japan, 104 0045
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, NO 0424
    • Novartis Investigative Site
• United States
  • California
    • San Francisco, California, United States, 94143
      • UCSF Medical Center .
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine/Winship Cancer Institute SC CTL019
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center Hematology and Oncology SC - CTL019B2207J
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center SC - CTL019C2201
  • Maryland
    • Baltimore, Maryland, United States, 21287-0013
      • Sidney Kimmel Comprehensive Cancer Center SC-2
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Uni of Michigan Health System SC CTL019
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University James Cancer Hospital &
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University Oregon Health & Sci Uni
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Perelman School of Medicine
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center SC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

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 Names: 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Main Cohort	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))	60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients	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.	5 years
Time to Response (TTR) as Assessed by Independent Review Committee (Main Cohort & All Patients)	TTR is the time between date of CTL019 infusion until first documented response (CR or PR).	up to approx. 3.3 months
Duration of Overall Response (DOR) Per IRC	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).	up to approx. 60.1 months
Event Free Survival (EFS) Per Independent Review Committee	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.	up to approx. 61 months
Progression Free Survival (PFS) Per Independent Review Committee	PFS is the time from date of CTL019 infusion to the date of first documented disease progression or death due to any cause.	up to approx. 61 months
Overall Survival (OS) Per Independent Review Committee	OS is the time from date of CTL019 infusion to the date of death due to any cause.	60 months
Pharmacokinetics (Pk): Cmax	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.	60 months
Pharmacokinetics (Pk): Tmax	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.	60 months
Pharmacokinetics (Pk): AUC0-28d and 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.	0 - 28 days after infusion for AUC0-28d, 0 - 84 days after infusion for AUC0-84d
Pharmacokinetics (Pk): T1/2	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.	60 months
Pharmacokinetics (Pk): Clast	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.	60 months
Pharmacokinetics (Pk): Tlast	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.	60 months
Incidence of Immunogenicity to CTL019	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.	pre-infusion and at any time point post-baseline, up to duration of the study, up to 5 years

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.
• Cartron G, Fox CP, Liu FF, Kostic A, Hasskarl J, Li D, Bonner A, Zhang Y, Maloney DG, Kuruvilla J. Matching-adjusted indirect treatment comparison of chimeric antigen receptor T-cell therapies for third-line or later treatment of relapsed or refractory large B-cell lymphoma: lisocabtagene maraleucel versus tisagenlecleucel. Exp Hematol Oncol. 2022 Mar 25;11(1):17. doi: 10.1186/s40164-022-00268-z.
• Frigault MJ, Dietrich J, Gallagher K, Roschewski M, Jordan JT, Forst D, Plotkin SR, Cook D, Casey KS, Lindell KA, Depinho GD, Katsis K, Elder EL, Leick MB, Choi B, Horick N, Preffer F, Saylor M, McAfee S, O'Donnell PV, Spitzer TR, Dey B, DeFilipp Z, El-Jawahri A, Batchelor TT, Maus MV, Chen YB. Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial. Blood. 2022 Apr 14;139(15):2306-2315. doi: 10.1182/blood.2021014738.
• Schuster SJ, Tam CS, Borchmann P, Worel N, McGuirk JP, Holte H, Waller EK, Jaglowski S, Bishop MR, Damon LE, Foley SR, Westin JR, Fleury I, Ho PJ, Mielke S, Teshima T, Janakiram M, Hsu JM, Izutsu K, Kersten MJ, Ghosh M, Wagner-Johnston N, Kato K, Corradini P, Martinez-Prieto M, Han X, Tiwari R, Salles G, Maziarz RT. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1403-1415. doi: 10.1016/S1470-2045(21)00375-2. Epub 2021 Sep 10.
• Westin JR, Kersten MJ, Salles G, Abramson JS, Schuster SJ, Locke FL, Andreadis C. Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: Observations from the JULIET, ZUMA-1, and TRANSCEND trials. Am J Hematol. 2021 Oct 1;96(10):1295-1312. doi: 10.1002/ajh.26301. Epub 2021 Aug 13.
• Schuster SJ, Maziarz RT, Rusch ES, Li J, Signorovitch JE, Romanov VV, Locke FL, Maloney DG. Grading and management of cytokine release syndrome in patients treated with tisagenlecleucel in the JULIET trial. Blood Adv. 2020 Apr 14;4(7):1432-1439. doi: 10.1182/bloodadvances.2019001304.
• Maziarz RT, Schuster SJ, Romanov VV, Rusch ES, Li J, Signorovitch JE, Maloney DG, Locke FL. Grading of neurological toxicity in patients treated with tisagenlecleucel in the JULIET trial. Blood Adv. 2020 Apr 14;4(7):1440-1447. doi: 10.1182/bloodadvances.2019001305.
• Maziarz RT, Waller EK, Jaeger U, Fleury I, McGuirk J, Holte H, Jaglowski S, Schuster SJ, Bishop MR, Westin JR, Mielke S, Teshima T, Bachanova V, Foley SR, Borchmann P, Salles GA, Zhang J, Tiwari R, Pacaud LB, Ma Q, Tam CS. Patient-reported long-term quality of life after tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 2020 Feb 25;4(4):629-637. doi: 10.1182/bloodadvances.2019001026.
• Awasthi R, Pacaud L, Waldron E, Tam CS, Jager U, Borchmann P, Jaglowski S, Foley SR, van Besien K, Wagner-Johnston ND, Kersten MJ, Schuster SJ, Salles G, Maziarz RT, Anak O, Del Corral C, Chu J, Gershgorin I, Pruteanu-Malinici I, Chakraborty A, Mueller KT, Waller EK. Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL. Blood Adv. 2020 Feb 11;4(3):560-572. doi: 10.1182/bloodadvances.2019000525.
• Bishop MR, Maziarz RT, Waller EK, Jager U, Westin JR, McGuirk JP, Fleury I, Holte H, Borchmann P, Del Corral C, Tiwari R, Anak O, Awasthi R, Pacaud L, Romanov VV, Schuster SJ. Tisagenlecleucel in relapsed/refractory diffuse large B-cell lymphoma patients without measurable disease at infusion. Blood Adv. 2019 Jul 23;3(14):2230-2236. doi: 10.1182/bloodadvances.2019000151.
• Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jager U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak O, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. doi: 10.1056/NEJMoa1804980. Epub 2018 Dec 1.

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2015
• Primary Completion (Actual): December 22, 2022
• Study Completion (Actual): December 22, 2022

Study Registration Dates

• First Submitted: May 5, 2015
• First Submitted That Met QC Criteria: May 14, 2015
• First Posted (Estimated): May 15, 2015

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: DLBCL; CTL019; Chimeric antigen receptor; Diffuse large B-cell lymphoma; CAR T cells; CART; Relapsed/refractory; CART19
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Agents; Antineoplastic Agents, Immunological; Tisagenlecleucel
• Other Study ID Numbers: CCTL019C2201; 2014-003060-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No