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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03568461
• Collaborator: (none)
• Enrollment: 98
• Locations: 30
• Arm: 1
• Anticipated Duration (Months): 78.3
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Follicular Lymphoma	Biological: tisagenlecleucel	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 98 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Nov 12, 2018
• Actual Primary Completion Date: Nov 24, 2020
• Anticipated Study Completion Date: May 22, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CTL019 All patients who received tisagenlecleucel infusion.	Biological: tisagenlecleucel; Tisagenlecleucel is single infusion.; Other Names: CTL019

Outcome Measures

Primary Outcome Measures

1. Complete Response Rate (CRR) Per Independent Review Committee (IRC) Assessment [1 year]

   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 classification response criteria. The radiological response is first obtained from CT and PET studies according to the Lugano 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 scan. The possible outcomes for PET response are complete metabolic response (CMR), partial metabolic response (PMR), no metabolic response (NMR), or progressive metabolic disease (PMD).

Secondary Outcome Measures

1. Overall Response Rate (ORR) Per IRC Assessment [1 year]

   Overall response rate is defined as the percentage of participants with a best overall disease response of complete response (CR) or partial response (PR).

2. Duration of Response (DOR) Per IRC [1 year]

   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).

3. Progression Free Survival (PFS) [2 years]

   Time from tisagenlecleucel infusion to first documented disease progression or death due to any cause

4. Overall Survival (OS) [2 years]

   Time from tisagenlecleucel infusion to death due to any cause

5. Tisagenlecleucel Transgene Concentration [2 years]

   Transgene concentration as detected by qPCR in target tissue

6. Cmax; Cellular Kinetic Parameter of Tisagenlecleucel [2 years]

   The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/ µg)

7. Tmax; Cellular Kinetic Parameter of Tisagenlecleucel [2 years]

   The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days)

8. AUC0-28; Cellular Kinetic Parameter of Tisagenlecleucel [2 years]

   The AUC from time zero to day 28, in peripheral blood (%*days or days*copies/ µg)

9. AUC0-84d; Cellular Kinetic Parameter of Tisagenlecleucel [2 years]

   The AUC from time zero to day 84, in peripheral blood (%*days or days*copies/ µg)

10. T1/2; Cellular Kinetic Parameter of Tisagenlecleucel [2 years]

    The half-life associated with the elimination phase slope of a semi logarithmic concentration-time curve (days) in peripheral blood

11. Tlast; Cellular Kinetic Parameter of Tisagenlecleucel [2 years]

    The last observed measureable timepoint after dose administration

12. Summary of Exposure of CD3+ Tisagenlecleucel Cells in Peripheral Blood [2 years]

    In vivo cellular kinetics of CD3+ tisagenlecleucel cells detected by flow cytometry

13. Humoral Immunogenicity [2 years]

    Antibody titers specific to the tisagenlecleucel molecule prior to and following infusion.

14. Cellular Immunogenicity [2 years]

    Presence of T lymphocytes activated by the tisagenlecleucel protein

15. Summary Scores of PRO Measured by SF-36v2 Quality of Life Questionnaire [2 years]

    Effect of tisagenlecleucel therapy on Patient reported outcomes

16. Summary Scores of PRO Measured by EQ-5D-3L Quality of Life Questionnaire [2 years]

    Effect of tisagenlecleucel therapy on Patient reported outcomes

17. Summary Scores of PRO Measured by FACT-Lym Quality of Life Questionnaire [2 years]

    Effect of tisagenlecleucel therapy on Patient reported outcomes

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center Dept.ofCityofHopeMedicalCtr(1)	Duarte	California	United States	91010 3000
2	UCSF Medical Center	San Francisco	California	United States	94143
3	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
4	University of Chicago Medical Center Hematology and Oncology	Chicago	Illinois	United States	60637
5	University of Kansas Hospital and Medical Center DeptofUofKansas CancerCenter-2	Kansas City	Kansas	United States	66160
6	Michigan Medicine University of Michigan	Ann Arbor	Michigan	United States	48109 5271
7	Oregon Health and Science University	Portland	Oregon	United States	97239
8	University of Pennsylvania Clinical Studies Unit Perelman Center for Adv Med	Philadelphia	Pennsylvania	United States	19104
9	MD Anderson Cancer Center SC	Houston	Texas	United States	77030
10	Novartis Investigative Site	Herston	Queensland	Australia	4029
11	Novartis Investigative Site	Melbourne	Victoria	Australia	3000
12	Novartis Investigative Site	Camperdown		Australia	NSW
13	Novartis Investigative Site	Linz		Austria	4020
14	Novartis Investigative Site	Gent		Belgium	9000
15	Novartis Investigative Site	Paris Cedex 10		France	75475
16	Novartis Investigative Site	Pierre Benite Cedex		France	69495
17	Novartis Investigative Site	Koeln		Germany	50937
18	Novartis Investigative Site	Muenchen		Germany	81377
19	Novartis Investigative Site	Ulm		Germany	89081
20	Novartis Investigative Site	Bologna	BO	Italy	40138
21	Novartis Investigative Site	Milano	MI	Italy	20132
22	Novartis Investigative Site	Fukuoka city	Fukuoka	Japan	812-8582
23	Novartis Investigative Site	Sapporo city	Hokkaido	Japan	060 8648
24	Novartis Investigative Site	Sendai city	Miyagi	Japan	980 8574
25	Amsterdam UMC, locatie AMC	Amsterdam		Netherlands	1105 AZ
26	Novartis Investigative Site	Oslo		Norway	NO 0424
27	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
28	Novartis Investigative Site	Madrid		Spain	28041
29	Novartis Investigative Site	Birmingham		United Kingdom	B15 2TH
30	Novartis Investigative Site	London		United Kingdom	SE5 9RS

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Mar 29, 2018
• Statistical Analysis Plan - May 7, 2021

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03568461
• Other Study ID Numbers: CCTL019E2202; 2017-004385-94
• First Posted: Jun 26, 2018
• Last Update Posted: Jul 22, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Refractory or relapsed Follicular Lymphoma; Refractory; Relapsed; Follicular lymphoma; CTL019; Tisagenlecleucel; Chimeric antigen receptor; CAR19; CAR-T
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular

Study Results

Participant Flow

Recruitment Details	90 patients were planned, 98 patients were enrolled and 97 patients were infused with tisagenlecleucel.
Pre-assignment Detail	During the Screening phase and prior to enrolment into the study, a patient's white blood cells were collected via leukapheresis.

Arm/Group Title	CTL019
Arm/Group Description	All patients who were enrolled in the study
Period Title: Overall Study
STARTED	98
Treated	97
Discontinued Prior to Transfusion With Tisagenlecleucel	1
COMPLETED	80
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	CTL019
Arm/Group Description	All patients who were enrolled in the study
Overall Participants	98
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.5 (10.34)
Sex: Female, Male (Count of Participants)
Female	33 33.7%
Male	65 66.3%
Race/Ethnicity, Customized (Count of Participants)
White	74 75.5%
Asian: Japanese	9 9.2%
Asian: Indian	2 2%
Asian: Missing	2 2%
Black or African American	1 1%
Missing	10 10.2%

Outcome Measures

1. Primary Outcome

Title	Complete Response Rate (CRR) Per Independent Review Committee (IRC) Assessment
Description	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 classification response criteria. The radiological response is first obtained from CT and PET studies according to the Lugano 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 scan. The possible outcomes for PET response are complete metabolic response (CMR), partial metabolic response (PMR), no metabolic response (NMR), or progressive metabolic disease (PMD).
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Efficacy analysis set (EAS): All the patients who received tisagenlecleucel, and had measurable disease at baseline per IRC. Non-measurable disease at baseline is defined as absence of index lesion at baseline disease evaluation (i.e. no disease at baseline).

Arm/Group Title	CTL019
Arm/Group Description	All patients who received tisagenlecleucel infusion
Measure Participants	94
Number (95% Confidence Interval) [Percentage of participants]	69.1 70.5%

2. Secondary Outcome

Title	Overall Response Rate (ORR) Per IRC Assessment
Description	Overall response rate is defined as the percentage of participants with a best overall disease response of complete response (CR) or partial response (PR).
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Efficacy analysis set (EAS): All the patients who received tisagenlecleucel, and had measurable disease at baseline per IRC. Non-measurable disease at baseline is defined as absence of index lesion at baseline disease evaluation (i.e. no disease at baseline).

Arm/Group Title	CTL019
Arm/Group Description	All patients who received tisagenlecleucel infusion
Measure Participants	94
Number (95% Confidence Interval) [Percentage or participants]	86.2 88%

3. Secondary Outcome

Title	Duration of Response (DOR) Per IRC
Description	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).
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Efficacy analysis set (EAS): All the patients who received tisagenlecleucel, and had measurable disease at baseline per IRC. Non-measurable disease at baseline is defined as absence of index lesion at baseline disease evaluation (i.e. no disease at baseline).

Arm/Group Title	CTL019
Arm/Group Description	All patients who received tisagenlecleucel infusion
Measure Participants	94
Median (95% Confidence Interval) [months]	NA

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Time from tisagenlecleucel infusion to first documented disease progression or death due to any cause
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Overall Survival (OS)
Description	Time from tisagenlecleucel infusion to death due to any cause
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Tisagenlecleucel Transgene Concentration
Description	Transgene concentration as detected by qPCR in target tissue
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Cmax; Cellular Kinetic Parameter of Tisagenlecleucel
Description	The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/ µg)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Tmax; Cellular Kinetic Parameter of Tisagenlecleucel
Description	The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	AUC0-28; Cellular Kinetic Parameter of Tisagenlecleucel
Description	The AUC from time zero to day 28, in peripheral blood (%*days or days*copies/ µg)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	AUC0-84d; Cellular Kinetic Parameter of Tisagenlecleucel
Description	The AUC from time zero to day 84, in peripheral blood (%*days or days*copies/ µg)
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	T1/2; Cellular Kinetic Parameter of Tisagenlecleucel
Description	The half-life associated with the elimination phase slope of a semi logarithmic concentration-time curve (days) in peripheral blood
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Tlast; Cellular Kinetic Parameter of Tisagenlecleucel
Description	The last observed measureable timepoint after dose administration
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Summary of Exposure of CD3+ Tisagenlecleucel Cells in Peripheral Blood
Description	In vivo cellular kinetics of CD3+ tisagenlecleucel cells detected by flow cytometry
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Humoral Immunogenicity
Description	Antibody titers specific to the tisagenlecleucel molecule prior to and following infusion.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Cellular Immunogenicity
Description	Presence of T lymphocytes activated by the tisagenlecleucel protein
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

Title	Summary Scores of PRO Measured by SF-36v2 Quality of Life Questionnaire
Description	Effect of tisagenlecleucel therapy on Patient reported outcomes
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Secondary Outcome

Title	Summary Scores of PRO Measured by EQ-5D-3L Quality of Life Questionnaire
Description	Effect of tisagenlecleucel therapy on Patient reported outcomes
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Secondary Outcome

Title	Summary Scores of PRO Measured by FACT-Lym Quality of Life Questionnaire
Description	Effect of tisagenlecleucel therapy on Patient reported outcomes
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse Events were reported from first dose of study treatment until Month 12 (plus 30 days post-tisagenlecleucel infusion)
Adverse Event Reporting Description	Adverse Event (AE): Any sign or symptom that occurs during treatment plus 30 days post treatment.
Arm/Group Title	CTL019
Arm/Group Description	All patients who received tisagenlecleucel infusion.
All Cause Mortality
	CTL019
	Affected / at Risk (%)	# Events
Total	7/97 (7.2%)
Serious Adverse Events
	CTL019
	Affected / at Risk (%)	# Events
Total	42/97 (43.3%)
Blood and lymphatic system disorders
Anaemia	1/97 (1%)
Febrile neutropenia	6/97 (6.2%)
Neutropenia	2/97 (2.1%)
Cardiac disorders
Ventricular fibrillation	1/97 (1%)
Eye disorders
Blindness	1/97 (1%)
Gastrointestinal disorders
Gastrointestinal ulcer	1/97 (1%)
Glossitis	1/97 (1%)
Nausea	1/97 (1%)
Stomatitis	1/97 (1%)
Vomiting	1/97 (1%)
General disorders
Catheter site haemorrhage	1/97 (1%)
Pyrexia	3/97 (3.1%)
Immune system disorders
Cytokine release syndrome	19/97 (19.6%)
Graft versus host disease in gastrointestinal tract	1/97 (1%)
Infections and infestations
Bacteraemia	1/97 (1%)
COVID-19	1/97 (1%)
COVID-19 pneumonia	1/97 (1%)
Diverticulitis	1/97 (1%)
Human herpesvirus 6 encephalitis	1/97 (1%)
Localised infection	1/97 (1%)
Lower respiratory tract infection	1/97 (1%)
Parainfluenzae virus infection	1/97 (1%)
Perirectal abscess	1/97 (1%)
Pneumonia	8/97 (8.2%)
Pneumonia haemophilus	1/97 (1%)
Progressive multifocal leukoencephalopathy	1/97 (1%)
Pseudomonal bacteraemia	1/97 (1%)
Sepsis	1/97 (1%)
Injury, poisoning and procedural complications
Infusion related reaction	2/97 (2.1%)
Investigations
Platelet count decreased	1/97 (1%)
Metabolism and nutrition disorders
Failure to thrive	1/97 (1%)
Musculoskeletal and connective tissue disorders
Muscle spasms	1/97 (1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/97 (1%)
Bowen's disease	1/97 (1%)
Malignant melanoma	1/97 (1%)
Squamous cell carcinoma	2/97 (2.1%)
Nervous system disorders
Encephalopathy	2/97 (2.1%)
Headache	1/97 (1%)
Immune effector cell-associated neurotoxicity syndrome	1/97 (1%)
Syncope	1/97 (1%)
Renal and urinary disorders
Acute kidney injury	1/97 (1%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/97 (1%)
Dyspnoea	1/97 (1%)
Pleural effusion	2/97 (2.1%)
Pneumothorax	1/97 (1%)
Other (Not Including Serious) Adverse Events
	CTL019
	Affected / at Risk (%)	# Events
Total	94/97 (96.9%)
Blood and lymphatic system disorders
Anaemia	24/97 (24.7%)
Febrile neutropenia	8/97 (8.2%)
Leukopenia	8/97 (8.2%)
Lymphopenia	8/97 (8.2%)
Neutropenia	41/97 (42.3%)
Thrombocytopenia	19/97 (19.6%)
Gastrointestinal disorders
Abdominal pain	7/97 (7.2%)
Constipation	14/97 (14.4%)
Diarrhoea	21/97 (21.6%)
Nausea	14/97 (14.4%)
Vomiting	8/97 (8.2%)
General disorders
Asthenia	6/97 (6.2%)
Chills	7/97 (7.2%)
Fatigue	16/97 (16.5%)
Pyrexia	16/97 (16.5%)
Immune system disorders
Cytokine release syndrome	30/97 (30.9%)
Hypogammaglobulinaemia	14/97 (14.4%)
Infections and infestations
Nasopharyngitis	6/97 (6.2%)
Sinusitis	5/97 (5.2%)
Upper respiratory tract infection	7/97 (7.2%)
Investigations
Lymphocyte count decreased	9/97 (9.3%)
Neutrophil count decreased	17/97 (17.5%)
Platelet count decreased	10/97 (10.3%)
SARS-CoV-2 test negative	6/97 (6.2%)
Weight decreased	6/97 (6.2%)
White blood cell count decreased	21/97 (21.6%)
Metabolism and nutrition disorders
Decreased appetite	7/97 (7.2%)
Hyperglycaemia	5/97 (5.2%)
Hypokalaemia	9/97 (9.3%)
Hypomagnesaemia	8/97 (8.2%)
Hypophosphataemia	9/97 (9.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	10/97 (10.3%)
Back pain	8/97 (8.2%)
Muscle spasms	6/97 (6.2%)
Myalgia	8/97 (8.2%)
Pain in extremity	5/97 (5.2%)
Nervous system disorders
Dizziness	7/97 (7.2%)
Headache	24/97 (24.7%)
Psychiatric disorders
Insomnia	6/97 (6.2%)
Respiratory, thoracic and mediastinal disorders
Cough	12/97 (12.4%)
Dyspnoea	5/97 (5.2%)
Pleural effusion	5/97 (5.2%)
Productive cough	5/97 (5.2%)
Skin and subcutaneous tissue disorders
Dry skin	5/97 (5.2%)
Pruritus	9/97 (9.3%)
Rash	6/97 (6.2%)
Vascular disorders
Hypertension	5/97 (5.2%)
Hypotension	8/97 (8.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e. data from all sites) in clinical trial or disclosure of trial results in their entirety.