Efficacy and Safety of Tisagenlecleucel in Adult Patients With Refractory or Relapsed Follicular Lymphoma (ELARA)

A Phase II, Single Arm, Multicenter Open Label Trial to Determine the Efficacy and Safety of Tisagenlecleucel (CTL019) in Adult Patients With Refractory or Relapsed Follicular Lymphoma

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

Study Overview

• Status: Completed
• Conditions: Follicular Lymphoma
• Intervention / Treatment: Biological: tisagenlecleucel

Detailed Description

This single-arm, open label study had the following sequential phases: Screening, Pretreatment, Treatment and Follow-up. In the Pre-treatment phase, the patient could undergo bridging therapy (optional) and lymphodepleting (LD) chemotherapy. Treatment and Follow-up Phase included tisagenlecleucel infusion, and safety and efficacy follow-up for at least 24 months. For all the patients who received tisagenlecleucel infusion, additional survival follow-up was to be performed to determine survival status every 3 months.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Herston, Australia, QLD 4006
    • Novartis Investigative Site
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Novartis Investigative Site
• Austria
  • Linz, Austria, 4020
    • Novartis Investigative Site
• Belgium
  • Ghent, Belgium, 9000
    • Novartis Investigative Site
• France
  • Paris, France, 75475
    • Novartis Investigative Site
  • Pierre-Bénite, France, 69495
    • Novartis Investigative Site
• Germany
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Bavaria
    • Munich, Bavaria, Germany, 81377
      • Novartis Investigative Site
  • North Rhine-Westphalia
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • Novartis Investigative Site
• Italy
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • MI
    • Milan, MI, Italy, 20132
      • Novartis Investigative Site
• Japan
  • Fukuoka, Japan, 8128582
    • Novartis Investigative Site
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8648
      • Novartis Investigative Site
  • Miyagi
    • Sendai, Miyagi, Japan, 9808574
      • Novartis Investigative Site
• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1081 HV
      • Novartis Investigative Site
• Norway
  • Norway
    • Oslo, Norway, Norway, 0310
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Seville, Spain, 41013
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Novartis Investigative Site
• United States
  • California
    • Duarte, California, United States, 91010 3000
      • City of Hope National Medical Center
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
  • Florida
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center and Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Uni of Chi Medi Ctr Hema and Onco
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Univ of Kansas Hosp and Med Ctr
  • Michigan
    • Ann Arbor, Michigan, United States, 48109 5271
      • Michigan Med University of Michigan
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Clinical
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Refractory or relapsed Follicular Lymphoma (Grade 1, 2, 3A)
• Radiographically measurable disease at screening

Exclusion Criteria:

• Evidence of histologic transformation
• Follicular Lymphoma Grade 3B
• Prior anti-CD19 therapy
• Prior gene therapy
• Prior adoptive T cell therapy
• Prior allogeneic hematopoietic stem cell transplant
• Active CNS involvement by malignancy

Other protocol-defined Inclusion/Exclusion criteria may apply.

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: CTL019; All patients who received tisagenlecleucel infusion.	Biological: tisagenlecleucel; Tisagenlecleucel is single infusion.; Other Names: CTL019

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response Rate (CRR) Per Independent Review Committee (IRC) Assessment	Complete response rate was defined as the percentage of participants with a best overall response (BOR) of complete response (CR) recorded from tisagenlecleucel infusion until progressive disease or start of new anticancer therapy, whichever came first. CRR was determined by an independent review committee (IRC) and was based on Lugano 2014 classification response criteria. The radiological response is first obtained from CT and PET studies according to the Lugano 2014 criteria. CT response is based on anatomical measurements of index/non-index/new lesions and spleen length. The possible response outcomes are complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). PET response based on a 5-point scale (5PS) or Deauville score. The possible outcomes for PET response are complete metabolic response (CMR), partial metabolic response (PMR), no metabolic response (NMR), or progressive metabolic disease (PMD).	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) Per IRC Assessment	Overall response rate is defined as the percentage of participants with a best overall disease response of complete response (CR) or partial response (PR). Response was evaluated per Lugano 2014 classification response criteria. The radiological response is first obtained from CT and PET studies according to the Lugano 2014 criteria. CT response is based on anatomical measurements of index/non-index/new lesions and spleen length. The possible response outcomes are complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). PET response based on a 5-point scale (5PS) or Deauville score. The possible outcomes for PET response are complete metabolic response (CMR), partial metabolic response (PMR), no metabolic response (NMR), or progressive metabolic disease (PMD).	1 year
Duration of Response (DOR) Per IRC Assessment	Duration of response (DOR) applied only to participants whose best overall disease response was CR or PR. It is defined as the time from the date of first documented disease response (CR or PR) to the date of first documented progression or death due to follicular lymphoma (FL). DOR was estimated using the Kaplan-Meier method.	approx. 60 months
Duration of Response (DOR) for Complete Response (CR) Only Per IRC Assessment	Duration of response (DOR) applied only to participants whose best overall disease response was complete response (CR) only. It is defined as the time from the date of first documented disease response (CR only) to the date of first documented progression or death due to follicular lymphoma (FL). DOR was estimated using the Kaplan-Meier method.	approx. 60 months
Progression Free Survival (PFS) Per IRC Assessment	Progression free survival is the time from tisagenlecleucel infusion to first documented disease progression or death due to any cause. PFS was estimated using the Kaplan-Meier method.	up to 61.7 months
Overall Survival (OS)	Overall Survival is the time from tisagenlecleucel infusion to death due to any cause. OS was estimated using the Kaplan-Meier method.	up to 65.8 months
Tisagenlecleucel Transgene Concentration Levels as Measured by Quantitative Polymerase Chain Reaction (qPCR) Method, by Clinical Response Per IRC Assessment	This is the summary of cellular kinetic concentrations for tisagenlecleucel (CTL019) transgene levels in peripheral blood and bone marrow following infusion.	Month 60 (peripheral blood), Month 6 (bone marrow)
Cmax; Cellular Kinetic Parameter of Tisagenlecleucel Transgene Levels by qPCR, Based on Clinical Response IRC Assessment	Cmax is the maximum (peak) observed in peripheral blood after single dose administration. Actual sampling times were taken into consideration for the calculation of cellular kinetic parameters parameters.	up to 60 months after infusion
Tmax; Cellular Kinetic Parameter of Tisagenlecleucel Transgene Levels by qPCR, Based on Clinical Response by IRC Assessment	Tmax is the time to reach maximum (peak) peripheral blood after single dose administration (days). Actual sampling times were taken into consideration for the calculation of cellular kinetic parameters.	up to 60 months after infusion
AUC0-28d and AUC0-84d; Cellular Kinetic Parameter of Tisagenlecleucel Transgene Levels by qPCR, Based on Clinical Response by IRC Assessment	AUC0-28 is the area under curve (AUC) from time zero to day 28 in peripheral blood. AUC0-84d is the AUC from time zero to day 84 in peripheral blood. Actual sampling times were taken into consideration for the calculation of cellular kinetic parameters.	0 to 28 days after infusion, 0 to 84 days after infusion
AUC0-28d and AUC0-84d; Cellular Kinetic Parameter for Tisagenlecleucel by Flow Cytometry, Based on Clinical Response by IRC Assessment	Exposure is summarized as area under the curve (AUC) from time 0 to 28 days (AUC0-28d) and from time to 84 days (AUC0-84d). The cellular kinetic parameters were estimated from the percentages of CD3+/CTL019+ cells obtained from flow cytometry. Flow cytometry measures the surface expression of chimeric antigen receptors (CARs) on T cells.	AUC0-28d: from time of infusion to 28 days post-dose; AUC0-84d: from time of infusion to 84 days post-infusion
Cmax; Cellular Kinetic Parameter for Tisagenlecleucel by Flow Cytometry, Based on Clinical Response by IRC Assessment	Cmax is the maximum (peak) observed in peripheral blood after single dose administration. Actual sampling times were taken into consideration for the calculation of cellular kinetic parameters parameters.	From pre-dose until 60 months after infusion
Summary of Exposure of CD3+ Tisagenlecleucel Cells in Peripheral Blood for Tmax	In vivo cellular kinetics of CD3+/CTL019+ levels tisagenlecleucel cells detected by flow cytometry base on best overall response (BOR). The cellular kinetic parameters were estimated from the percentages of CD3+/CTL019+ cells obtained from flow cytometry. Flow cytometry measures the surface expression of chimeric antigen receptors (CARs) on T cells.	From pre-dose until 60 months after infusion
Humoral Immunogenicity: Number of Participants With Anti-mCAR19 Antibodies, Per IRC Assessment	Antibody titers specific to the tisagenlecleucel molecule prior to and following infusion. Percentage of participants who tested positive for anti-mCAR19 antibodies at any time post-baseline. A participant was only defined as positive for tisagenlecleucel treatment-induced or -boosted anti-mCAR19 antibodies when the anti-mCAR19 antibody median fluorescence intensity (MFI) at any time post-infusion was at least 2.28-fold higher than pre-infusion levels for patients whose baseline status was positive (boosted) or if the baseline status was negative, but any post-baseline interpretation was positive (induced).	at any time post-baseline, up to 24 months post-infusion
Cellular Immunogenicity: Percentage of Interferon Gamma (IFNg+) Cells by Flow Cytometry Per IRC Assessment	Activation of T-cells in peripheral blood mononuclear cells collected from participants in response to mCAR19-derived peptides was used to assess the cellular immunogenicity against tisagenlecleucel. T-cell activation was measured by the percentage of interferon gamma (IFNg+) cells by flow cytometry. Cellular responses to mCART peptides were measured pre-infusion (enrollment) and post-tisagenlecleucel infusion. Pool 1 and Pool 2 are a pool of 60 peptides (peptides 1-60) and 59 peptides (peptides 61-119) , respectively, corresponding to the CTL019 transgene product. Together, they comprised 119 peptides spanning the CTL019 transgene product and were used to stimulate PBMCs to detect antigen-specific T cell responses via intracellular cytokine staining.	pre-infusion (pre-Lymph depletion evaluation), 24 months post-infusion
Summary Scores of Patient-reported Outcome (PRO) Measured by SF-36v2 Quality of Life Questionnaire by Visit	Effect of tisagenlecleucel therapy on patient reported outcomes were reported using the Short Form Health Survey (SF-36) v2 form. The SF-36 v2 is a widely used and extensively studied instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) were computed by summing the item responses on the questions for each domain in accordance with the respective scoring method provided by the developers. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. A high score defines a more favorable health state.	Baseline (BL) Month (M) 3, M3, M6, M9, M12, M18, M24
Summary Scores of PRO Measured by SF-36v2 Quality of Life Questionnaire Reported by Change From Baseline	Effect of tisagenlecleucel therapy on patient reported outcomes were reported using the Short Form Health Survey (SF-36) v2 form. The SF-36 v2 is a widely used and extensively studied instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) were computed by summing the item responses on the questions for each domain in accordance with the respective scoring method provided by the developers. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. A high score defines a more favorable health state.	Change from baseline (CFB) M3, CFB M6, CFB M9, CFB M12, CFB M18, CFB M24
Health Status Measured by EQ-5D-3L Questionnaire	Effect of tisagenlecleucel therapy on patient-reported outcomes was assessed using the EuroQol 5-Dimension, 3-Level instrument (EQ-5D-3L). The EQ-5D-3L is a widely used, self-administered questionnaire designed to evaluate health status in adults. It consists of two sections. The first includes one item for each of the five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Patients rate each dimension as "no problems" (level 1), "some problems" (level 2), or "extreme problems" (level 3). This record summarizes, for each of the five dimensions, the number of patients falling into each response level.	Baseline (BL), Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, Month 36
Summary Scores of PRO Measured by EQ-VAS Quality of Life Questionnaire by Visit	Effect of tisagenlecleucel therapy on patient reported outcomes were reported using the EQ-VAS (EuroQol Visual Analogue Scale). The EQ-VAS is a 20 cm vertical, 0-100 numerical scale used alongside the EQ-5D questionnaire to measure a patient's self-rated health. It anchors "best imaginable health" (100) at the top and "worst imaginable health" (0) at the bottom, providing a quick, subjective, quantitative, and global assessment of health status on the day of survey. The second section of the questionnaire measures self-rated (global) health status utilizing a vertically oriented visual analogue scale where 100 represents the "best possible health state" and 0 represents the "worst possible health state."	Baseline (BL) Month (M) 3, M6, M9, M12, M18, M24, M36
Summary Scores of PRO Measured by EQ-VAS Quality of Life Questionnaire Reported by Change From Baseline	Effect of tisagenlecleucel therapy on patient reported outcomes were reported using the EQ-VAS (EuroQol Visual Analogue Scale). The EQ-VAS is a 20 cm vertical, 0-100 numerical scale used alongside the EQ-5D questionnaire to measure a patient's self-rated health. It anchors "best imaginable health" (100) at the top and "worst imaginable health" (0) at the bottom, providing a quick, subjective, quantitative, and global assessment of health status on the day of survey	Baseline (BL), M3 change from baseline (CFB), M6 CFB, M9 CFB, M12 CFB, M18 CFB, M24 CFB, M36 CFB
Summary Scores of PRO Measured by FACT-Lym Quality of Life Questionnaire	The effect of tisagenlecleucel therapy on patient-reported outcomes was assessed using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) questionnaire, which measures quality of life in participants with lymphoma. FACT-Lym is composed of the FACT-G (27 items across Physical, Social/Family, Emotional, and Functional Well-Being, plus Additional Concerns) and a 15-item lymphoma-specific subscale. All items use a five-point self-administered response scale (0-4), with higher scores indicating better quality of life. The possible score ranges are as follows: - Physical Well-Being (PWB): 0-28 - Social/Family Well-Being (SWB): 0-28 - Emotional Well-Being (EWB): 0-24 - Functional Well-Being (FWB): 0-28 - Lym Subscale (15 items): 0-60 - Lymphoma Trial Outcome Index (TOI: PWB + FWB + Lym): 0-116 - FACT-G Total (PWB + SWB + EWB + FWB): 0-108 - FACT-Lym Total (FACT-G + Lym): 0-168 In all cases, higher scores indicate better outcomes within the corresponding domain.	Baseline (BL) Month (M) 3, M6, M9, M12, M18, M24, M36
Summary Scores of PRO Measured by FACT-Lym Quality of Life Questionnaire Reported by Change From Baseline	The effect of tisagenlecleucel therapy on patient-reported outcomes was assessed using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) questionnaire, which measures quality of life in participants with lymphoma. FACT-Lym is composed of the FACT-G (27 items across Physical, Social/Family, Emotional, and Functional Well-Being, plus Additional Concerns) and a 15-item lymphoma-specific subscale. All items use a five-point self-administered response scale (0-4), with higher scores indicating better quality of life. The possible score ranges are as follows: - Physical Well-Being (PWB): 0-28 - Social/Family Well-Being (SWB): 0-28 - Emotional Well-Being (EWB): 0-24 - Functional Well-Being (FWB): 0-28 - Lym Subscale (15 items): 0-60 - Lymphoma Trial Outcome Index (TOI: PWB + FWB + Lym): 0-116 - FACT-G Total (PWB + SWB + EWB + FWB): 0-108 - FACT-Lym Total (FACT-G + Lym): 0-168 In all cases, higher scores indicate better outcomes within the corresponding domain.	Baseline (BL), M3 change from baseline (CFB), M6 CFB, M9 CFB, M12 CFB, M18 CFB, M24 CFB, M36 CFB

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Salles G, Schuster SJ, Dreyling M, Fischer L, Kuruvilla J, Patten PEM, von Tresckow B, Smith SM, Jimenez-Ubieto A, Davis KL, Anjos C, Chu J, Zhang J, Lobetti Bodoni C, Thieblemont C, Fowler NH, Dickinson M, Martinez-Lopez J, Wang Y, Link BK. Efficacy comparison of tisagenlecleucel vs usual care in patients with relapsed or refractory follicular lymphoma. Blood Adv. 2022 Nov 22;6(22):5835-5843. doi: 10.1182/bloodadvances.2022008150.
• Fowler NH, Dickinson M, Dreyling M, Martinez-Lopez J, Kolstad A, Butler J, Ghosh M, Popplewell L, Chavez JC, Bachy E, Kato K, Harigae H, Kersten MJ, Andreadis C, Riedell PA, Ho PJ, Perez-Simon JA, Chen AI, Nastoupil LJ, von Tresckow B, Ferreri AJM, Teshima T, Patten PEM, McGuirk JP, Petzer AL, Offner F, Viardot A, Zinzani PL, Malladi R, Zia A, Awasthi R, Masood A, Anak O, Schuster SJ, Thieblemont C. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. 2022 Feb;28(2):325-332. doi: 10.1038/s41591-021-01622-0. Epub 2021 Dec 17.
• Dreyling M, Fowler NH, Dickinson M, Martinez-Lopez J, Kolstad A, Butler J, Ghosh M, Popplewell L, Chavez JC, Bachy E, Kato K, Harigae H, Kersten MJ, Andreadis C, Riedell PA, Ho PJ, Perez-Simon JA, Chen AI, Nastoupil LJ, von Tresckow B, Maria Ferreri AJ, Teshima T, Patten PEM, McGuirk JP, Petzer AL, Offner F, Viardot A, Zinzani PL, Malladi R, Paule I, Zia A, Awasthi R, Han X, Germano D, O'Donovan D, Ramos R, Maier HJ, Masood A, Thieblemont C, Schuster SJ. Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update. Blood. 2024 Apr 25;143(17):1713-1725. doi: 10.1182/blood.2023021567.

Helpful Links

• A Plain Language Trial Summary is available on www.novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2018
• Primary Completion (Actual): November 24, 2020
• Study Completion (Actual): May 28, 2025

Study Registration Dates

• First Submitted: May 24, 2018
• First Submitted That Met QC Criteria: June 13, 2018
• First Posted (Actual): June 26, 2018

Study Record Updates

• Last Update Posted (Actual): July 9, 2026
• Last Update Submitted That Met QC Criteria: July 7, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: CAR-T; Relapsed; Refractory; CTL019; Follicular lymphoma; Chimeric antigen receptor; Tisagenlecleucel; Refractory or relapsed Follicular Lymphoma; CAR19
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Recurrence; Lymphoma, Follicular; Antineoplastic Agents, Immunological; Antineoplastic Agents; tisagenlecleucel
• Other Study ID Numbers: CCTL019E2202; 2017-004385-94 (EudraCT Number); 2023-508127-13-00 (Registry Identifier: EU CTIS)

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 expert 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 is currently available according to the 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