Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients

NCT02445248 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: CCTL019C22012014-003060-20
• Study Type: interventional
• Target: 115
• Locations: 9 countries
• Sites: 24

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.

Conditions

Diffuse Large B-cell Lymphoma (DLBCL)

Keywords

Diffuse large B-cell lymphoma; DLBCL; Relapsed/refractory; CTL019; CART19; CART; CAR T cells; Chimeric antigen receptor

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients

  5 years

• Time to Response (TTR) as Assessed by Independent Review Committee (Main Cohort & All Patients)

  up to approx. 3.3 months

• Duration of Overall Response (DOR) Per IRC

  up to approx. 60.1 months

• Event Free Survival (EFS) Per Independent Review Committee

  up to approx. 61 months

• Progression Free Survival (PFS) Per Independent Review Committee

  up to approx. 61 months

Study Arms (1)

Tisagenlecleucel

EXPERIMENTAL

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

Biological: Tisagenlecleucel; Drug: Lymphodepleting chemotherapy

Interventions

Tisagenlecleucel BIOLOGICAL

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.

Also known as: CTL019

Tisagenlecleucel

Lymphodepleting chemotherapy DRUG

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).

Tisagenlecleucel

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (26)

UCSF Medical Center .

San Francisco, California, 94143, United States

Location

Emory University School of Medicine/Winship Cancer Institute SC CTL019

Atlanta, Georgia, 30322, United States

Location

University of Chicago Medical Center Hematology and Oncology SC - CTL019B2207J

Chicago, Illinois, 60637, United States

Location

University of Kansas Cancer Center SC - CTL019C2201

Westwood, Kansas, 66205, United States

Location

Sidney Kimmel Comprehensive Cancer Center SC-2

Baltimore, Maryland, 21287-0013, United States

Location

Uni of Michigan Health System SC CTL019

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

The Ohio State University James Cancer Hospital &

Columbus, Ohio, 43210, United States

Location

Oregon Health Sciences University Oregon Health & Sci Uni

Portland, Oregon, 97239, United States

Location

University of Pennsylvania Perelman School of Medicine

Philadelphia, Pennsylvania, 19104, United States

Location

MD Anderson Cancer Center SC

Houston, Texas, 77030, United States

Location

Novartis Investigative Site

Melbourne, Victoria, 3000, Australia

Location

Novartis Investigative Site

Camperdown, NSW, Australia

Location

Novartis Investigative Site

Vienna, A 1090, Austria

Location

Novartis Investigative Site

Hamilton, Ontario, L8V 5C2, Canada

Location

Novartis Investigative Site

Montreal, Quebec, H1T 2M4, Canada

Location

Novartis Investigative Site

Pierre-Bénite, 69495, France

Location

Novartis Investigative Site

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Novartis Investigative Site

Würzburg, 97080, Germany

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Fukuoka, Fukuoka, 812-8582, Japan

Location

Novartis Investigative Site

Sapporo, Hokkaido, 060 8648, Japan

Location

Novartis Investigative Site

Chuo Ku, Tokyo, 104 0045, Japan

Location

Novartis Investigative Site

Amsterdam, 1105 AZ, Netherlands

Location

Novartis Investigative Site

Oslo, NO 0424, Norway

Location

Related Publications (12)

• Maziarz RT, Bishop MR, Tam CS, Borchmann P, Worel N, McGuirk JP, Holte H, Waller EK, Jaglowski S, Andreadis C, Foley SR, Westin JR, Fleury I, Ho PJ, Mielke S, Teshima T, Janakiram M, Hsu J, Izutsu K, Kersten MJ, Ghosh M, Wagner-Johnston N, Kato K, Corradini P, Ma W, Han X, Nuortti M, Awasthi R, Mundt KE, Majdan M, Maier HJ, Jegerlehner A, Salles G, Schuster SJ. Five-Year Analysis of the JULIET Trial of Tisagenlecleucel in Patients With Relapsed/Refractory Large B-Cell Lymphoma. J Clin Oncol. 2026 Jan 10;44(2):86-91. doi: 10.1200/JCO-25-00507. Epub 2025 Nov 18.

  PMID: 41252666 DERIVED

• 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.

  PMID: 35337365 DERIVED

• 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.

  PMID: 35167655 DERIVED

• 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.

  PMID: 34516954 DERIVED

• 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.

  PMID: 34515338 DERIVED

• 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.

  PMID: 34310745 DERIVED

• 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.

  PMID: 32271899 DERIVED

• 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.

  PMID: 32271898 DERIVED

• 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.

  PMID: 32074277 DERIVED

• 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.

  PMID: 32045475 DERIVED

• 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.

  PMID: 31332046 DERIVED

• 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.

  PMID: 30501490 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Recurrence

Interventions

tisagenlecleucel

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Clinical Disclosure Office
• Organization: Novartis Pharmaceuticals

novartis.email@novartis.com

862-778-3000

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: May 5, 2015
• First Posted: May 15, 2015
• Study Start: July 29, 2015
• Primary Completion: December 22, 2022
• Study Completion: December 22, 2022
• Last Updated: April 18, 2024
• Results First Posted: April 18, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share

Locations

AU (1); DE (2); FR (1); US (12); NL (1); NO (1); IT (1); JP (3); CA (2)