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

• ClinicalTrials.gov Identifier: NCT02445248
• Recruitment Status: Completed
• First Posted: May 15, 2015
• Last Update Posted: January 31, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: May 5, 2015
• First Posted Date: May 15, 2015
• Last Update Posted Date: January 31, 2023
• Actual Study Start Date: July 29, 2015
• Actual Primary Completion Date: December 22, 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: April 12, 2018): Overall Response Rate (ORR) [ Time Frame: 5 years ]
• Original Primary Outcome Measures (submitted: May 14, 2015): Overall Response Rate(ORR) [ Time Frame: 5 years ]

Current Secondary Outcome Measures (submitted: December 3, 2015)

• Incidence and severity of adverse events (AEs) [ 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 ]
• In vivo cellular Pharmacokinetic (PK) profile of CTL019 transduced cells into target tissues [ Time Frame: 5 years ]
• Incidence of immunogenicity to CTL019 [ Time Frame: 5 years ]
• Number of Participants with presence of exposure to replication-competent lentivirus (RCL) as Assessed by quantitative polymerase chain reaction (qPCR) [ Time Frame: 5 years ]
• Prevalence of immunogenicity to CTL019 [ Time Frame: 5 years ]

Original Secondary Outcome Measures (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: Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients
• Official 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)
• 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: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Diffuse Large B-cell Lymphoma (DLBCL)

Intervention

• Biological: Tisagenlecleucel
  A single infusion of 5 x 10^8 viable CTL019 transduced cells, which will be administered via intravenous infusion.
  Other Name: CTL019
• Drug: Lymphodepleting chemotherapy
  Prior to CTL019 cell infusion, an additional lymphodepleting chemotherapy cycle is planned. The use of any additional chemotherapy prior to the recommended lymphodepleting chemotherapy will be at the discretion of the investigator and dependent on the patient's disease burden. Lymphodepleting chemotherapy should be 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 proposed lymphodepleting regimen is: Fludarabine (25 mg/m2 intravenously [i.v.] daily for 3 doses) and cyclophosphamide (250 mg/m2 i.v. daily for 3 doses starting with the first dose of fludarabine).

Study Arms

Experimental: Tisagenlecleucel

Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who will receive tisagenlecleucel.

Interventions:

• Biological: Tisagenlecleucel
• Drug: Lymphodepleting chemotherapy

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 9, 2020): 115
• Original Estimated Enrollment (submitted: May 14, 2015): 100
• Actual Study Completion Date: December 22, 2022
• Actual Primary Completion Date: December 22, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 m2

  • 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/mm3
    • Absolute lymphocyte count (ALC) ≥ 300/mm3
    • Platelets ≥ 50.000//mm3
    • 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 ASCT
• 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 CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: < 6 - 12 mg/m2/day hydrocortisone or equivalent
  • Immunosuppression: Any immunosuppressive medication must be stopped ≥ 4 weeks prior to enrollment
  • Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of infusion
  • 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
• Investigational medicinal product within the last 30 days prior to screening
• Pregnant or nursing (lactating) women
• Intolerance to the excipients of the CTL019 cell product
• Cardiac arrhythmia not controlled with medical management
• Patients on oral anticoagulation therapy
• Prior treatment with any adoptive T cell therapy
• Patients with active neurological auto immune or inflammatory disorders(e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis)

Other protocol-related inclusion/exclusion may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Canada, France, Germany, Italy, Japan, Netherlands, Norway, United States

Administrative Information

• NCT Number: NCT02445248
• Other Study ID Numbers: 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

• 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: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: January 2023