ELIANA: Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02435849
• Collaborator: (none)
• Enrollment: 97
• Locations: 25
• Arm: 1
• Anticipated Duration (Months): 91.7
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL.

Condition or Disease	Intervention/Treatment	Phase
B-cell Acute Lymphoblastic Leukemia	Biological: CTL019	Phase 2

Detailed Description

This was a initially a one cohort, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL. This main cohort completed enrollment. Two new cohorts were added via an amendment, Cohort 1 for high risk B-cell ALL patients at first relapse, and Cohort 2 for feasibility and safety of CTL019 in high risk B-cell ALL in patients that relapsed <6 months post allo-HSCT. Due to lack of recruitment, both of these cohorts have halted recruitment. This decision was not related to any safety issue.

The study had the following sequential phases: Screening, Pre-Treatment (Cell Product Preparation & Lymphodepleting Chemotherapy), Treatment and Primary Follow-up, Secondary Follow-up (if applicable) and Survival Follow-up. The total duration of the study is 5 years from CTL019 cell infusion.

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell Acute Lymphoblastic Leukemia
• Actual Study Start Date: Apr 8, 2015
• Actual Primary Completion Date: Jan 21, 2020
• Anticipated Study Completion Date: Nov 28, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single dose of CTL019 Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).	Biological: CTL019; Tisagenlecleucel was administered as a single iv infusion. Dose: 2.0 to 5.0x106 tisagenlecleucel per kg body weight (for patients ≤ 50 kg) or 1.0 to 2.5x108 tisagenlecleucel (for patients >50 kg).

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Overall Remission Rate (ORR) as Determined by IRC Assessment. [during the 3 months after tisagenlecleucel administration]

   Evaluating the efficacy of tisagenlecleucel therapy from all manufacturing facilities as measured by overall remission rate (ORR) during the 3 months after tisagenlecleucel administration. ORR included complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by an Independent Review Committee ( IRC) assessment.

Secondary Outcome Measures

1. Percentage of Patients Who Achieve Best Overall Response (BOR) or CR or CRi With an MRD Negative Bone Marrow by Central Analysis Using qPCR [3 months]

2. Percentage of Patients Who Achieve CR or CRi at Month 6 Without SCT Between CTL019 Infusion and Month 6 Response Assessment. [6 months]

3. Duration of Remission (DOR) [60 months]

4. Percentage of Patients Who Achieve CR or CRi With Minimal Residual Disease Negative Bone Marrow [3 months]

5. Relapse-free Survival [60 months]

6. Event-free Survival [60 months]

7. Overall Survival [60 months]

8. Response at Day 28 +/- 4 Days [1 month]

9. Impact of Baseline Tumor Burden on Response [60 months]

10. Percentage of Patient Who Achieve CR or CRi and Then Proceed to SCT While in Remission Before Month 6 Response Assessment [6 months]

11. Quality of Response Using MRD Disease Assessments Before Treatment at Day 28 +/-4 Days After Treatment Using Central Assessments by qPCR and Before SCT by Local Assessment (Flow or PCR) [60 months]

12. Safety of CTL019 Therapy [60 months]

13. Characterize in Vivo Cellular PK Profile of CTL019 Cells in Target Tissues [60 months]

14. Prevalence and Incidence of Immunogenicity to CTL019 [60 months]

15. Effects of CTL019 Therapy on Patient Reported Outcomes [60 months]

16. Derivation of a Score to Predict Cytokine Release Syndrome [3 months]

17. Describe the Profile of Soluble Immune Factors That May be Key to Cytokine Release Syndrome [6 months]

18. Describe Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion for Safety Monitoring [3 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria (Main Cohort closed for an enrollment):

• Relapsed or refractory pediatric B-cell ALL

1. 2nd or greater Bone Marrow (BM) relapse OR.

2. Any BM relapse after allogeneic stem cell transplantation (SCT) and must be ≥ 6 months from SCT at the time of CTL019 infusion OR.

3. Primary refractory as defined by not achieving a CR after 2 cycles of a standard chemotherapy regimen or chemorefractory as defined by not achieving a CR after 1 cycle of standard chemotherapy for relapsed leukemia OR.

4. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI), or if TKI therapy is contraindicated OR.

5. Ineligible for allogeneic SCT.

• For relapsed patients, documentation of CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of study entry.

• Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.

• Life expectancy > 12 weeks.

• Age 3 at the time of screening to age 21 at the time of initial diagnosis

• Must have an apheresis product of non-mobilized cells received and accepted by the manufacturing site.

Exclusion Criteria (Main Cohort closed for an enrollment):

• Isolated extra-medullary disease relapse

• Patients with concomitant genetic syndrome: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down Syndrome will not be excluded.

• Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)

• Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease

• Treatment with any prior gene therapy product

• Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy

• Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening

• Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening

• Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD).

• Active CNS involvement by malignancy, defined by CNS-3 per NCCN guidelines.

• Patient has an investigational medicinal product within the last 30 days prior to screening.

• Pregnant or nursing (lactating) women.

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception from signing informed consent and through at least 12 months after the CTL019 infusion

• Sexually active males must use a condom during intercourse from signing informed consent to at least 12 months after the CTL019 infusion

Inclusion Criteria (Cohort 1 closed for an enrollment):

1. B-cell acute lymphoblastic leukemia and:

• First relapse AND hypodiploid cytogenetics: fewer than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a hypodiploid clone OR

• First relapse AND t(17;19) with defined TCF3-HLF fusion OR

• First relapse with any cytogenetics provided the relapse occurred ≤ 36 months of initial diagnosis AND MRD at end of reinduction therapy is ≥0.01% by flow cytometry (local assessment)

• For relapsed patients, documentation of CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of study entry.

• Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.

• Life expectancy > 12 weeks.

• Age up to 25 years at the time of screening.

• Must have an apheresis product of non-mobilized cells received and accepted by the manufacturing site.

Exclusion Criteria (Cohort 1 closed for an enrollment):

• Isolated extra-medullary disease relapse

• Patients with concomitant genetic syndrome: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down Syndrome will not be excluded.

• Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)

• Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease

• Treatment with any prior gene therapy product

• Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy

• Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening

• Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening

• Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD).

• Active CNS involvement by malignancy, defined by CNS-3 per NCCN guidelines.

• Patient has an investigational medicinal product within the last 30 days prior to screening.

• Pregnant of nursing (lactating) women.

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception from signing informed consent and through at least 12 months after the CTL019 infusion

• Sexually active males must use a condom during intercourse from signing informed consent to at least 12 months after the CTL019 infusion

Inclusion Criteria (Cohort 2 closed for an enrollment):

1. B-cell acute lymphoblastic leukemia and:

• Any BM relapse after allogeneic stem cell transplantation (allo-HSCT) and must be < 6 months from HSCT at the time of CTL019 infusion

• For relapsed patients, documentation of CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of study entry.

• Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.

• Life expectancy > 12 weeks.

• Age up to 25 years at the time of screening.

• Must have an apheresis product of non-mobilized cells received and accepted by the manufacturing site.

Exclusion Criteria (Cohort 2 closed for an enrollment):

• Isolated extra-medullary disease relapse

• Patients with concomitant genetic syndrome: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down Syndrome will not be excluded.

• Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)

• Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease

• Treatment with any prior gene therapy product

• Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy

• Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening

• Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening

• Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD).

• Active CNS involvement by malignancy, defined by CNS-3 per NCCN guidelines.

• Patient has an investigational medicinal product within the last 30 days prior to screening.

• Pregnant or nursing (lactating) women

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception from signing informed consent and through at least 12 months after the CTL019 infusion

• Sexually active males must use a condom during intercourse from signing informed consent to at least 12 months after the CTL019 infusion

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Childrens Hospital Los Angeles SC CTL019	Los Angeles	California	United States	90027
2	Stanford University Medical Center SC -	Stanford	California	United States	94304
3	Children's Healthcare of Atlanta SC CTL019	Atlanta	Georgia	United States	30342
4	University of Michigan SC	Ann Arbor	Michigan	United States	48109-2800
5	University of Minnesota SC	Minneapolis	Minnesota	United States	55455
6	Mercy Children's Kansas University	Kansas City	Missouri	United States	64108
7	Duke Unversity Medical Center	Durham	North Carolina	United States	27705
8	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229-3039
9	Oregon Health & Science University Doernbecher Children's Hosp.	Portland	Oregon	United States	97239-3098
10	The Childrens Hospital of Philadelphia CHOP	Philadelphia	Pennsylvania	United States	19104
11	Children's Medical Center of Dallas SC	Dallas	Texas	United States	75235
12	University of Utah	Salt Lake City	Utah	United States	84108
13	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
14	Novartis Investigative Site	Parkville	Victoria	Australia	3052
15	Novartis Investigative Site	Wien		Austria	A 1090
16	Novartis Investigative Site	Gent		Belgium	9000
17	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1X8
18	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1C5
19	Novartis Investigative Site	Paris Cedex 10	Cedex 10	France	75475
20	Novartis Investigative Site	Paris Cedex		France	75019
21	Novartis Investigative Site	Frankfurt		Germany	60590
22	Novartis Investigative Site	Monza	MB	Italy	20900
23	Novartis Investigative Site	Kyoto		Japan	606 8507
24	Novartis Investigative Site	Oslo		Norway	0424
25	Novartis Investigative Site	Esplugues de Llobregat	Barcelona	Spain	08950

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - Mar 21, 2019
• Statistical Analysis Plan - May 27, 2019

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02435849
• Other Study ID Numbers: CCTL019B2202; 2013-003205-25
• First Posted: May 6, 2015
• Last Update Posted: Jun 28, 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: Pediatric; ALL; Cell therapy; Lymphoblastic Leukemia; Acute; High Risk; Childhood; CTL019; tisagenlecleucel; Pediatric patients; r/r B-cell ALL; high risk B-cell ALL at first relapse; high risk B-cell ALL that relapsed < 6 months post allo-HSCT
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid

Study Results

Participant Flow

Recruitment Details

Patients were recruited between 08-Apr-2015 (FPFV) and 14-Jan-2020 (LPFV). 79 patients were infused in the main cohort, Cohort 1 had only 1 patient infused, and cohort 2 had no patients infused. Only main cohort analysis is presented through the data cutoff of 13-Apr-2018. At the time of this cutoff, all patients had completed at least 3 months of follow-up post-infusion and therefore were evaluable for the primary outcome measure.

Pre-assignment Detail

"Enrolled" means all eligibility criteria were met and apheresis was accepted by the manufacturing facility. Patients could discontinue the trial after enrollment and prior to tisagenlecleucel infusion. Although 97 patients were enrolled, only 79 were infused as 18 discontinued prior to infusion.

Arm/Group Title	Single Dose of CTL019
Arm/Group Description	Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).
Period Title: Overall Study
STARTED	97
Enrolled and Infused	79
Enrolled But Not Infused	18
Discontinued Study Follow-up	34
COMPLETED	0
NOT COMPLETED	97

Baseline Characteristics

Arm/Group Title	Single Dose of CTL019
Arm/Group Description	Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).
Overall Participants	79
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	12.0 (5.38)
Sex: Female, Male (Count of Participants)
Female	34 43%
Male	45 57%
Race/Ethnicity, Customized (Number) [Number]
White	58 73.4%
Asian	10 12.7%
Other	11 13.9%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Overall Remission Rate (ORR) as Determined by IRC Assessment.
Description	Evaluating the efficacy of tisagenlecleucel therapy from all manufacturing facilities as measured by overall remission rate (ORR) during the 3 months after tisagenlecleucel administration. ORR included complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by an Independent Review Committee ( IRC) assessment.
Time Frame	during the 3 months after tisagenlecleucel administration

Outcome Measure Data

Analysis Population Description

FAS: The Full analysis set comprised all patients who received infusion of tisagenlecleucel.

Arm/Group Title	Single Dose of CTL019
Arm/Group Description	Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).
Measure Participants	79
Number (95% Confidence Interval) [Percentage of participants]	82.3 104.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single Dose of CTL019
	Comments
	Type of Statistical Test	Other
	Comments	testing the null hypothesis that ORR within 3 months is less than or equal to 20%
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Clopper-Pearson
	Comments

2. Secondary Outcome

Title	Percentage of Patients Who Achieve Best Overall Response (BOR) or CR or CRi With an MRD Negative Bone Marrow by Central Analysis Using qPCR
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Percentage of Patients Who Achieve CR or CRi at Month 6 Without SCT Between CTL019 Infusion and Month 6 Response Assessment.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Duration of Remission (DOR)
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Percentage of Patients Who Achieve CR or CRi With Minimal Residual Disease Negative Bone Marrow
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Relapse-free Survival
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Event-free Survival
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Overall Survival
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Response at Day 28 +/- 4 Days
Time Frame	1 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Impact of Baseline Tumor Burden on Response
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Percentage of Patient Who Achieve CR or CRi and Then Proceed to SCT While in Remission Before Month 6 Response Assessment
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Quality of Response Using MRD Disease Assessments Before Treatment at Day 28 +/-4 Days After Treatment Using Central Assessments by qPCR and Before SCT by Local Assessment (Flow or PCR)
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Safety of CTL019 Therapy
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Characterize in Vivo Cellular PK Profile of CTL019 Cells in Target Tissues
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Prevalence and Incidence of Immunogenicity to CTL019
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

Title	Effects of CTL019 Therapy on Patient Reported Outcomes
Time Frame	60 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Secondary Outcome

Title	Derivation of a Score to Predict Cytokine Release Syndrome
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Secondary Outcome

Title	Describe the Profile of Soluble Immune Factors That May be Key to Cytokine Release Syndrome
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Secondary Outcome

Title	Describe Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion for Safety Monitoring
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse Event (AE) timeframe: Adverse events were collected during the post-infusion period (starting at the day of first infusion until the end of the study), up to maximum duration of 60 months for each patient
Adverse Event Reporting Description	AE description: Any sign or symptom that occurs during the post-infusion period (starting at the day of first infusion of CTL019 until the end of the study)
Arm/Group Title	Single Dose of CTL019
Arm/Group Description	Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisageneceucel
All Cause Mortality
	Single Dose of CTL019
	Affected / at Risk (%)	# Events
Total	25/79 (31.6%)
Serious Adverse Events
	Single Dose of CTL019
	Affected / at Risk (%)	# Events
Total	62/79 (78.5%)
Blood and lymphatic system disorders
Coagulopathy	1/79 (1.3%)
Disseminated intravascular coagulation	3/79 (3.8%)
Febrile neutropenia	15/79 (19%)
Pancytopenia	1/79 (1.3%)
Thrombocytopenia	1/79 (1.3%)
Cardiac disorders
Atrioventricular block first degree	1/79 (1.3%)
Cardiac arrest	3/79 (3.8%)
Cardiac failure	2/79 (2.5%)
Left ventricular dysfunction	1/79 (1.3%)
Tachycardia	1/79 (1.3%)
Gastrointestinal disorders
Abdominal compartment syndrome	1/79 (1.3%)
Constipation	1/79 (1.3%)
Crohn's disease	1/79 (1.3%)
Diarrhoea	2/79 (2.5%)
Nausea	1/79 (1.3%)
Neutropenic colitis	1/79 (1.3%)
Pancreatitis	2/79 (2.5%)
Vomiting	1/79 (1.3%)
General disorders
Multiple organ dysfunction syndrome	2/79 (2.5%)
Non-cardiac chest pain	1/79 (1.3%)
Pyrexia	7/79 (8.9%)
Systemic inflammatory response syndrome	1/79 (1.3%)
Hepatobiliary disorders
Cholestasis	1/79 (1.3%)
Hepatomegaly	1/79 (1.3%)
Immune system disorders
Cytokine release syndrome	50/79 (63.3%)
Drug hypersensitivity	2/79 (2.5%)
Haemophagocytic lymphohistiocytosis	1/79 (1.3%)
Infections and infestations
Bacteraemia	1/79 (1.3%)
Bronchopulmonary aspergillosis	1/79 (1.3%)
Candida infection	1/79 (1.3%)
Cystitis	1/79 (1.3%)
Cytomegalovirus infection	1/79 (1.3%)
Device related infection	1/79 (1.3%)
Encephalitis	2/79 (2.5%)
Encephalitis viral	2/79 (2.5%)
Enterobacter infection	1/79 (1.3%)
Gastroenteritis	2/79 (2.5%)
Herpes zoster	2/79 (2.5%)
Human herpesvirus 6 infection	1/79 (1.3%)
Klebsiella infection	1/79 (1.3%)
Mastoiditis	1/79 (1.3%)
Meningitis bacterial	1/79 (1.3%)
Meningitis pneumococcal	1/79 (1.3%)
Metapneumovirus infection	1/79 (1.3%)
Otitis externa	1/79 (1.3%)
Otitis media	1/79 (1.3%)
Parainfluenzae virus infection	1/79 (1.3%)
Pharyngitis streptococcal	1/79 (1.3%)
Pneumocystis jirovecii pneumonia	1/79 (1.3%)
Pneumonia	2/79 (2.5%)
Pneumonia respiratory syncytial viral	1/79 (1.3%)
Pneumonia viral	1/79 (1.3%)
Pulmonary mycosis	1/79 (1.3%)
Respiratory syncytial virus infection	2/79 (2.5%)
Rhinovirus infection	2/79 (2.5%)
Sepsis	1/79 (1.3%)
Septic shock	2/79 (2.5%)
Sinusitis	1/79 (1.3%)
Soft tissue infection	1/79 (1.3%)
Staphylococcal bacteraemia	2/79 (2.5%)
Staphylococcal sepsis	1/79 (1.3%)
Upper respiratory tract infection	3/79 (3.8%)
Urinary tract infection	1/79 (1.3%)
Varicella zoster virus infection	1/79 (1.3%)
Viral upper respiratory tract infection	1/79 (1.3%)
Injury, poisoning and procedural complications
Infusion related reaction	1/79 (1.3%)
Vasoplegia syndrome	1/79 (1.3%)
Investigations
Aspartate aminotransferase increased	2/79 (2.5%)
Blood bilirubin increased	1/79 (1.3%)
Blood uric acid increased	1/79 (1.3%)
Electrocardiogram QT prolonged	1/79 (1.3%)
Metabolism and nutrition disorders
Dehydration	1/79 (1.3%)
Hypercalcaemia	1/79 (1.3%)
Hyperkalaemia	1/79 (1.3%)
Hypernatraemia	1/79 (1.3%)
Hyperphosphataemia	1/79 (1.3%)
Hypokalaemia	1/79 (1.3%)
Malnutrition	1/79 (1.3%)
Metabolic acidosis	1/79 (1.3%)
Tumour lysis syndrome	2/79 (2.5%)
Musculoskeletal and connective tissue disorders
Back pain	3/79 (3.8%)
Haemarthrosis	1/79 (1.3%)
Rhabdomyolysis	1/79 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome	1/79 (1.3%)
Nervous system disorders
Cerebral haemorrhage	1/79 (1.3%)
Cognitive disorder	1/79 (1.3%)
Dysarthria	1/79 (1.3%)
Encephalopathy	1/79 (1.3%)
Headache	1/79 (1.3%)
Hydrocephalus	1/79 (1.3%)
Nervous system disorder	1/79 (1.3%)
Seizure	1/79 (1.3%)
Psychiatric disorders
Delirium	1/79 (1.3%)
Mental status changes	2/79 (2.5%)
Renal and urinary disorders
Acute kidney injury	5/79 (6.3%)
Renal failure	1/79 (1.3%)
Renal tubular necrosis	1/79 (1.3%)
Reproductive system and breast disorders
Endometriosis	1/79 (1.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	2/79 (2.5%)
Acute respiratory failure	1/79 (1.3%)
Bronchial oedema	1/79 (1.3%)
Dyspnoea	1/79 (1.3%)
Epistaxis	1/79 (1.3%)
Hypoxia	5/79 (6.3%)
Pleural effusion	2/79 (2.5%)
Pulmonary oedema	1/79 (1.3%)
Respiratory distress	2/79 (2.5%)
Respiratory failure	5/79 (6.3%)
Vascular disorders
Hypotension	8/79 (10.1%)
Venoocclusive disease	1/79 (1.3%)
Other (Not Including Serious) Adverse Events
	Single Dose of CTL019
	Affected / at Risk (%)	# Events
Total	79/79 (100%)
Blood and lymphatic system disorders
Anaemia	25/79 (31.6%)
Coagulopathy	4/79 (5.1%)
Disseminated intravascular coagulation	5/79 (6.3%)
Febrile neutropenia	13/79 (16.5%)
Neutropenia	11/79 (13.9%)
Thrombocytopenia	8/79 (10.1%)
Cardiac disorders
Tachycardia	17/79 (21.5%)
Endocrine disorders
Adrenal insufficiency	4/79 (5.1%)
Gastrointestinal disorders
Abdominal pain	11/79 (13.9%)
Abdominal pain upper	5/79 (6.3%)
Constipation	13/79 (16.5%)
Diarrhoea	21/79 (26.6%)
Mouth haemorrhage	4/79 (5.1%)
Nausea	20/79 (25.3%)
Pancreatitis	4/79 (5.1%)
Vomiting	24/79 (30.4%)
General disorders
Chills	7/79 (8.9%)
Face oedema	8/79 (10.1%)
Fatigue	16/79 (20.3%)
Generalised oedema	4/79 (5.1%)
Oedema peripheral	7/79 (8.9%)
Pain	5/79 (6.3%)
Pyrexia	29/79 (36.7%)
Hepatobiliary disorders
Hepatic function abnormal	5/79 (6.3%)
Hyperbilirubinaemia	5/79 (6.3%)
Immune system disorders
Cytokine release syndrome	37/79 (46.8%)
Haemophagocytic lymphohistiocytosis	4/79 (5.1%)
Hypogammaglobulinaemia	30/79 (38%)
Immunodeficiency	4/79 (5.1%)
Infections and infestations
Clostridium difficile infection	4/79 (5.1%)
Conjunctivitis	6/79 (7.6%)
Gastroenteritis	4/79 (5.1%)
Nail infection	4/79 (5.1%)
Nasopharyngitis	6/79 (7.6%)
Otitis media	4/79 (5.1%)
Rhinovirus infection	7/79 (8.9%)
Sinusitis	5/79 (6.3%)
Staphylococcal infection	5/79 (6.3%)
Upper respiratory tract infection	13/79 (16.5%)
Injury, poisoning and procedural complications
Infusion related reaction	4/79 (5.1%)
Investigations
Activated partial thromboplastin time prolonged	4/79 (5.1%)
Alanine aminotransferase increased	18/79 (22.8%)
Aspartate aminotransferase increased	18/79 (22.8%)
Blood bilirubin increased	12/79 (15.2%)
Blood creatinine increased	5/79 (6.3%)
Blood fibrinogen decreased	7/79 (8.9%)
Blood immunoglobulin A decreased	7/79 (8.9%)
Blood immunoglobulin M decreased	6/79 (7.6%)
Blood lactate dehydrogenase increased	5/79 (6.3%)
C-reactive protein increased	6/79 (7.6%)
Electrocardiogram QT prolonged	5/79 (6.3%)
International normalised ratio increased	9/79 (11.4%)
Lymphocyte count decreased	17/79 (21.5%)
Neutrophil count decreased	23/79 (29.1%)
Platelet count decreased	24/79 (30.4%)
Serum ferritin increased	8/79 (10.1%)
Weight increased	4/79 (5.1%)
White blood cell count decreased	24/79 (30.4%)
Metabolism and nutrition disorders
Decreased appetite	30/79 (38%)
Fluid overload	7/79 (8.9%)
Hyperglycaemia	8/79 (10.1%)
Hyperphosphataemia	4/79 (5.1%)
Hyperuricaemia	9/79 (11.4%)
Hypoalbuminaemia	11/79 (13.9%)
Hypocalcaemia	16/79 (20.3%)
Hypokalaemia	20/79 (25.3%)
Hypomagnesaemia	6/79 (7.6%)
Hypophosphataemia	18/79 (22.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	8/79 (10.1%)
Back pain	8/79 (10.1%)
Bone pain	4/79 (5.1%)
Musculoskeletal pain	5/79 (6.3%)
Myalgia	10/79 (12.7%)
Pain in extremity	17/79 (21.5%)
Nervous system disorders
Dizziness	4/79 (5.1%)
Encephalopathy	7/79 (8.9%)
Headache	27/79 (34.2%)
Seizure	4/79 (5.1%)
Somnolence	5/79 (6.3%)
Tremor	6/79 (7.6%)
Psychiatric disorders
Agitation	6/79 (7.6%)
Anxiety	13/79 (16.5%)
Confusional state	7/79 (8.9%)
Delirium	7/79 (8.9%)
Insomnia	5/79 (6.3%)
Renal and urinary disorders
Acute kidney injury	9/79 (11.4%)
Dysuria	4/79 (5.1%)
Respiratory, thoracic and mediastinal disorders
Cough	20/79 (25.3%)
Dyspnoea	6/79 (7.6%)
Epistaxis	5/79 (6.3%)
Hypoxia	16/79 (20.3%)
Nasal congestion	9/79 (11.4%)
Oropharyngeal pain	8/79 (10.1%)
Pleural effusion	6/79 (7.6%)
Pulmonary oedema	11/79 (13.9%)
Rhinorrhoea	5/79 (6.3%)
Tachypnoea	8/79 (10.1%)
Skin and subcutaneous tissue disorders
Dry skin	8/79 (10.1%)
Erythema	5/79 (6.3%)
Pruritus	7/79 (8.9%)
Rash	8/79 (10.1%)
Vascular disorders
Hypertension	15/79 (19%)
Hypotension	17/79 (21.5%)

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.