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Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients (ELIANA)

Primary Purpose

B-cell Acute Lymphoblastic Leukemia

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

CTL019

About this trial

This is an interventional treatment trial for B-cell Acute Lymphoblastic Leukemia focused on measuring 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

Eligibility Criteria

undefined - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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):

a. 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):

a. 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

Sites / Locations

Childrens Hospital Los Angeles SC CTL019
Stanford Universtiy Medical Center SC - CTL019B2205J - B2206
Children's Healthcare of Atlanta SC CTL019
University of Michigan .
University of Minnesota
Children s Mercy Hospital SC - CTL019B2205J
Duke Unversity Medical Center .
Oregon Health and Science University Doernbecher Children's Hosp.
The Childrens Hospital of Philadelphia CHOP
University of Texas Southwestern Medical Center .
University of Utah Clinical Trials Office SC - CTL019B2205J
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single dose of CTL019

Arm Description

Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).

Outcomes

Primary Outcome Measures

Percentage of Participants With Overall Remission Rate (ORR) as Determined by Independent Review Committee (IRC) Assessment.

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 assessment. Per response criteria defined by National Comprehensive Cancer Network (NCCN), American Society of Hematology (ASH) and International Working Group (IWG) guidelines. CR is defined as: Bone marrow <5% blasts, Peripheral blood: Neutrophils >1.0 x 10^9/L, and Platelets >100 x 10^9/L and Circulating blasts <1% and No evidence of extramedullary disease, at least 7 days transfusion independency. CRi is defined as all the prior criteria being met, except that the following exists: Neutrophils ≤1.0 x 10^9/L, and/or Platelets ≤100 x 10^9/L, and/or Platelet and/or neutrophil transfusions ≤7 days before the date of the peripheral blood sample for disease assessment.

Secondary Outcome Measures

Percentage of Participants With Overall Remission Rate (ORR) as Per IRC From US Manufacturing Facilities in the Main Cohort Only (Key Secondary)

These are the percentage of participants with ORR who achieved overall remission rate which includes complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by IRC assessment after having been infused with tisagenlecleucel from US manufacturing facilities.

Percentage of Participants With Best Overall Response (BOR) of CR or CRi With Minimal Residue Disease (MRD) Negative Bone Marrow From US Manufacturing Facility as Per IRC in the Main Cohort Only (Key Secondary)

These are the percentage of participants who achieved Best Overall Response (BOR) of complete response (CR) or complete response with incomplete blood count recovery (CRi) with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from US manufacturing facilities only, by IRC assessment.

Percentage of Participants With Best Overall Response (BOR) of CR or CRi With MRD Negative Bone Marrow by Flow Cytometry From All Manufacturing Facilities as Per IRC in the Main Cohort Only (Key Secondary)

These are the percentage of participants who achieved Best Overall Response (BOR) of CR or CRi with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from all manufacturing facilities by IRC assessment. MRD negative = MRD% < 0.01%

Percentage of Participants Who Achieved CR or CRi Without Hematopoietic Stem Cell Transplantation (HSCT)

These are the participants who achieved CR or CRi without HSCT between tisagenlecleucel (CTL019) infusion and Month 6 response assessment.

Percentage of Participants Who Achieved CR or CRi and Then Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) While in Remission Prior to Month 6 Resoonse

These are the participants who achieved CR or CRi and then proceeded to HSCT while in remission prior to Month 6 response assessment

Number of Participants Who Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) After Tisagenlecleucel (CTL019) Infusion

These are the participants who achieved CR or CRi and then proceeded to SCT after being infused by tisagenlecleucel.

Duration of Remission (DOR)

DOR is the time from achievement of CR or CRi at any time post-infusion, whichever occurs first, to relapse or death.

Site of Involvement of Subsequent Relapse

Anatomical location of relapse in participants who achieved prior CR/CRi subsequent to tisagenlecleucel infusion.

Relapse-free Survival Per IRC Assessment

RFS is the time from achievement of CR or CRi at any time post-infusion, whichever occurs first, to relapse or death due to any cause during CR or CRi.

Event-free Survival Per IRC Assessment

EFS is the time from date of tisagenlecleucel infusion to the earliest of death, relapse or treatment failure.

Overall Survival (OS)

OS, is the time from date of tisagenlecleucel infusion to the date of death due to any reason.

Percentage of Participants Attaining CR or CRi at Day 28 +/- 4 Days Post Tisagenlecleucel (CTL019) Infusion by IRC Assessment

These are participants who had a day 28 response (CR or CRi response) by IRC assessment.

Response as a Function of Baseline Tumor Burden (Tumor Load) in Main Cohort Only

Percentage of participants who achieved BOR of CR or CRi by flow cytometry as a function of baseline bone marrow tumor burden.

Bone Marrow MRD Status by Flow Cytometry Per IRC Assessment

Percentage of participants who achieved CR or CRi response with bone marrow MRD negative (MRD < 0.01%) after tisagenlecleucel infusion by flow cytometry.

Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood by Day 28 Response by Independent Review Committee (IRC) Assessment

This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in peripheral blood.

Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow by Day 28 Response by IRC Assessment

This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in bone marrow.

Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Peripheral Blood by Day 28 Disease Response Per IRC Assessment

This is the summary cellular kinetic concentrations for CTL019 by flow cytometry in peripheral blood. It evaluated the persistence of transduced CTL019 cells post-infusion. Observation was up to Month 60 for peripheral blood.

Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Bone Marrow by Day 28 Response by IRC Assessment

This is the summary cellular kinetic concentrations for CTL019 by flow cytometry. It evaluated the persistence of transduced CTL019 cells post-infusion. Observation was up to Month 6 for bone marrow.

Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC

Cmax is the maximum (peak) observed in peripheral blood drug concentration after single dose administration reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas M60 is the actual timepoint for endpoint assessment. The reported Cmax is the summary of maximum level observed based on the data from each patient and based on all the data that's been collected for up to 60 months in a patient.

Pharmacokinetics (PK) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC

Tmax is the time to reach maximum (peak) peripheral blood drug concentration after single dose administration (days)", reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas M60 is the actual timepoint for endpoint assessment. The time frame of 60 months refers to the duration for which the data were reviewed to identify the time of Cmax for this measure.

Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC

AUC (area under curve) from day of infusion to day 28 or other disease assessment days, in peripheral blood (% or copies/μg x days), reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas 84 days is the actual timepoint for endpoint assessment. : AUC is defined based on the time window i.e., AUC from 0 to 84 days after infusion. Therefore, the time frame specifies the maximum time for up to which the data are used for estimation of AUC (84 days for AUC84d).

Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC

Persistence is defined as the time corresponding to last quantifiable transgene level in peripheral blood (Tlast), reported by CR/CRi, no response (NR), Unknown and by All participants. D28 refers to the timepoint for definition of responder populations, whereas M60 is the actual timepoint for endpoint assessment.

Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019)

This is defined as the percentage of participants who tested positive for anti-mCAR19 antibodies at any time post-baseline, reported by CR/CRi, no response (NR), Unknown and by All participants. .

Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire

The PedsQL questionnaire was for patients ≥ 8-years-old who achieved BOR as CR or CRi within 3 months and the questionnaire was on emotional, social, school, physical, and psychosocial health. Scores are transformed on a scale from 0 to 100, with the sum of all the items over the number of items answered on all the scales. The total scale score is the averaged value of scores of subscales, which means for each subscale and the total scale, the allowed ranges are 0-100. Higher scores on the PedsQL questionnaire for these subscales indicate consistent improvement of health-related quality of life (HRQol).

Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire

Results from the EQ-5D questionnaire is for number of participants who achieved CR or CRi at month 60. The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain & discomfort, anxiety & depression. Respondents are asked to choose the statement in each dimension that best describes their health status on the day surveyed. Their responses are coded as a number (1, 2, or 3) that corresponds to the respective level of severity: 1 indicates no problems, 2 some problems, and 3 severe problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the 5 dimensions can be combined into a 5-digit number that describes the patient's health state. The scores are then normalized to a value from 0-100 where higher scores = better HRQOL & fewer problems or symptoms.

Develop a Score Utilizing Clinical and Biomarker Data and Assess Its Ability for Early Prediction of Cytokine Release Syndrome (CRS)

Derivation of a score to predict cytokine release syndrome. Considering the complexity and challenges of building a scoring system based on limited data from the trial, this analysis was not performed.

Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (C Reactive Protein & Ferritin)

Profile of soluble immune factors of key inflammatory markers and cytokine parameters in blood by maximum CRS grade that may be key to cytokine release syndrome (CRS).

Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers)

Profile of soluble immune factors of key inflammatory markers and cytokine parameters in blood by maximum CRS grade that may be key to cytokine release syndrome (CRS).

Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion

Levels of B and T cells (blood and bone marrow) prior to and following CTL019 infusion for safety monitoring

Percentage of Participants With Overall Remission Rate (ORR) - From Fraunhofer Institute Manufacturing Facility

Percentage of Participants With Best Overall Response (BOR) of CR or CRi With Minimal Residue Disease (MRD) Negative Bone Marrow From Fraunhofer Institute Manufacturing Facility as Per IRC

These are the percentage of participants who achieved Best Overall Response (BOR) of CR or CRi with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from Fraunhofer Institute manufacturing facilities only, by IRC assessment.

Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood - Tisagenlecleucel Manufactured From Fraunhofer Institute

This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR, by disease response in blood by IRC assessment. The assessment of the efficacy, safety and in vivo cellular pharmacokinetics are for patients infused with tisagenlecleucel manufactured by Fraunhofer Institute.

Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow - Tisagenlecleucel Manufactured From Fraunhofer Institute

This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR, by disease response in bone marrow by IRC assessment. The assessment of the efficacy, safety and in vivo cellular pharmacokinetics are for patients infused with tisagenlecleucel manufactured by Fraunhofer Institute.

Full Information

NCT ID

NCT02435849

First Posted

April 16, 2015

Last Updated

September 25, 2023

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02435849

Brief Title

Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

Acronym

ELIANA

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

April 8, 2015 (Actual)

Primary Completion Date

January 21, 2020 (Actual)

Study Completion Date

November 17, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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.

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, Cohort 1 and Cohort 2 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. Efficacy analyses were performed only on the Main Cohort (n=79) who were infused with tisagenlecleucel. However, the data on disposition and demographics presented in this section includes all patients enrolled to the study (98) and all infused patients (80) (Main Cohort + Cohort 1). No patients were enrolled in Cohort 2.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

B-cell Acute Lymphoblastic Leukemia

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

80 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Single dose of CTL019

Arm Type

Experimental

Arm Description

Pediatric patients with relapsed or refractory B-cell ALL who were treated with single dose of tisagenlecleucel (CTL019).

Intervention Type

Biological

Intervention Name(s)

CTL019

Intervention Description

Tisagenlecleucel was administered as a single iv infusion. Dose: 2.0 to 5.0x10^6 tisagenlecleucel per kg body weight (for patients ≤ 50 kg) or 1.0 to 2.5x10^8 tisagenlecleucel (for patients >50 kg).

Primary Outcome Measure Information:

Title

Percentage of Participants With Overall Remission Rate (ORR) as Determined by Independent Review Committee (IRC) Assessment.

Description

Time Frame

during the 3 months after tisagenlecleucel administration

Secondary Outcome Measure Information:

Title

Percentage of Participants With Overall Remission Rate (ORR) as Per IRC From US Manufacturing Facilities in the Main Cohort Only (Key Secondary)

Description

Time Frame

3 months after tisagenlecleucel administration

Title

Description

Time Frame

3 months after tisagenlecleucel administration

Title

Description

Time Frame

3 months after tisagenlecleucel administration

Title

Percentage of Participants Who Achieved CR or CRi Without Hematopoietic Stem Cell Transplantation (HSCT)

Description

These are the participants who achieved CR or CRi without HSCT between tisagenlecleucel (CTL019) infusion and Month 6 response assessment.

Time Frame

6 months after tisagenlecleucel administration

Title

Percentage of Participants Who Achieved CR or CRi and Then Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) While in Remission Prior to Month 6 Resoonse

Description

These are the participants who achieved CR or CRi and then proceeded to HSCT while in remission prior to Month 6 response assessment

Time Frame

6 months

Title

Number of Participants Who Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) After Tisagenlecleucel (CTL019) Infusion

Description

These are the participants who achieved CR or CRi and then proceeded to SCT after being infused by tisagenlecleucel.

Time Frame

up to 6 months

Title

Duration of Remission (DOR)

Description

DOR is the time from achievement of CR or CRi at any time post-infusion, whichever occurs first, to relapse or death.

Time Frame

60 months

Title

Site of Involvement of Subsequent Relapse

Description

Anatomical location of relapse in participants who achieved prior CR/CRi subsequent to tisagenlecleucel infusion.

Time Frame

60 months

Title

Relapse-free Survival Per IRC Assessment

Description

RFS is the time from achievement of CR or CRi at any time post-infusion, whichever occurs first, to relapse or death due to any cause during CR or CRi.

Time Frame

60 months

Title

Event-free Survival Per IRC Assessment

Description

EFS is the time from date of tisagenlecleucel infusion to the earliest of death, relapse or treatment failure.

Time Frame

60 months

Title

Overall Survival (OS)

Description

OS, is the time from date of tisagenlecleucel infusion to the date of death due to any reason.

Time Frame

60 months

Title

Percentage of Participants Attaining CR or CRi at Day 28 +/- 4 Days Post Tisagenlecleucel (CTL019) Infusion by IRC Assessment

Description

These are participants who had a day 28 response (CR or CRi response) by IRC assessment.

Time Frame

1 month

Title

Response as a Function of Baseline Tumor Burden (Tumor Load) in Main Cohort Only

Description

Percentage of participants who achieved BOR of CR or CRi by flow cytometry as a function of baseline bone marrow tumor burden.

Time Frame

3 months

Title

Bone Marrow MRD Status by Flow Cytometry Per IRC Assessment

Description

Percentage of participants who achieved CR or CRi response with bone marrow MRD negative (MRD < 0.01%) after tisagenlecleucel infusion by flow cytometry.

Time Frame

28 days

Title

Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood by Day 28 Response by Independent Review Committee (IRC) Assessment

Description

This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in peripheral blood.

Time Frame

Month 60

Title

Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow by Day 28 Response by IRC Assessment

Description

This is the summary of cellular kinetic concentrations for Tisagenlecleucel (CTL019) transgene levels by qPCR in bone marrow.

Time Frame

Month 6

Title

Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Peripheral Blood by Day 28 Disease Response Per IRC Assessment

Description

Time Frame

Month 60

Title

Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Bone Marrow by Day 28 Response by IRC Assessment

Description

This is the summary cellular kinetic concentrations for CTL019 by flow cytometry. It evaluated the persistence of transduced CTL019 cells post-infusion. Observation was up to Month 6 for bone marrow.

Time Frame

Month 6

Title

Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC

Description

Time Frame

60 months

Title

Pharmacokinetics (PK) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC

Description

Time Frame

60 months

Title

Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC

Description

Time Frame

0 to 84 days after infusion

Title

Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC

Description

Time Frame

60 months

Title

Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019)

Description

This is defined as the percentage of participants who tested positive for anti-mCAR19 antibodies at any time post-baseline, reported by CR/CRi, no response (NR), Unknown and by All participants. .

Time Frame

At any time post-baseline, up to a max. of 60 months

Title

Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire

Description

Time Frame

Month 3, M6, M12, M24, M60

Title

Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire

Description

Time Frame

Month 60

Title

Develop a Score Utilizing Clinical and Biomarker Data and Assess Its Ability for Early Prediction of Cytokine Release Syndrome (CRS)

Description

Time Frame

3 months

Title

Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (C Reactive Protein & Ferritin)

Description

Profile of soluble immune factors of key inflammatory markers and cytokine parameters in blood by maximum CRS grade that may be key to cytokine release syndrome (CRS).

Time Frame

Maximum post-baseline (approx. 60 months)

Title

Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers)

Description

Profile of soluble immune factors of key inflammatory markers and cytokine parameters in blood by maximum CRS grade that may be key to cytokine release syndrome (CRS).

Time Frame

Maximum post-baseline (approx. 60 months)

Title

Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion

Description

Levels of B and T cells (blood and bone marrow) prior to and following CTL019 infusion for safety monitoring

Time Frame

Month 3, Month 12, Maximum post-baseline (approx. 60 months)

Title

Percentage of Participants With Overall Remission Rate (ORR) - From Fraunhofer Institute Manufacturing Facility

Description

Time Frame

60 months

Title

Percentage of Participants With Best Overall Response (BOR) of CR or CRi With Minimal Residue Disease (MRD) Negative Bone Marrow From Fraunhofer Institute Manufacturing Facility as Per IRC

Description

These are the percentage of participants who achieved Best Overall Response (BOR) of CR or CRi with an MRD-negative bone marrow by central analysis using flow cytometry among participants who received tisagenlecleucel from Fraunhofer Institute manufacturing facilities only, by IRC assessment.

Time Frame

3 months

Title

Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood - Tisagenlecleucel Manufactured From Fraunhofer Institute

Description

Time Frame

Month 60

Title

Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow - Tisagenlecleucel Manufactured From Fraunhofer Institute

Description

Time Frame

Month 3

10. Eligibility

Sex

All

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Relapsed or refractory pediatric B-cell ALL Adequate organ function For relapsed patients, documentation of CD19 tumor expression within 3 months of study entry. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening. Life expectancy > 12 weeks. Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening Signed written informed consent and assent forms Must meet the institutional criteria to undergo leukapheresis or have an acceptable, store leukapheresis product Must have an apheresis product of non-mobilized cells received and accepted by the manufacturing site. Cohort 1 only: First relapse AND hypodiploid cytogenetics 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) Exclusion Criteria 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 physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception for at least 12 months after the CTL019 infusion and after CAR T-cells are no longer present by qPCR on two consecutive tests Sexually active males must use a condom during intercourse at least 12 months after the CTL019 infusion after CAR T-cells are no longer present by qPCR on two consecutive tests

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Childrens Hospital Los Angeles SC CTL019

City

Los Angeles

State/Province

California

ZIP/Postal Code

90027

Country

United States

Facility Name

Stanford Universtiy Medical Center SC - CTL019B2205J - B2206

City

Stanford

State/Province

California

ZIP/Postal Code

94304

Country

United States

Facility Name

Children's Healthcare of Atlanta SC CTL019

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30342

Country

United States

Facility Name

University of Michigan .

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109-2800

Country

United States

Facility Name

University of Minnesota

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

Facility Name

Children s Mercy Hospital SC - CTL019B2205J

City

Kansas City

State/Province

Missouri

ZIP/Postal Code

64108

Country

United States

Facility Name

Duke Unversity Medical Center .

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27705

Country

United States

Facility Name

Oregon Health and Science University Doernbecher Children's Hosp.

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239-3098

Country

United States

Facility Name

The Childrens Hospital of Philadelphia CHOP

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

University of Texas Southwestern Medical Center .

City

Dallas

State/Province

Texas

ZIP/Postal Code

75235

Country

United States

Facility Name

University of Utah Clinical Trials Office SC - CTL019B2205J

City

Salt Lake City

State/Province

Utah

ZIP/Postal Code

84108

Country

United States

Facility Name

Novartis Investigative Site

City

Parkville

State/Province

Victoria

ZIP/Postal Code

3052

Country

Australia

Facility Name

Novartis Investigative Site

City

Wien

ZIP/Postal Code

A 1090

Country

Austria

Facility Name

Novartis Investigative Site

City

Gent

ZIP/Postal Code

9000

Country

Belgium

Facility Name

Novartis Investigative Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1X8

Country

Canada

Facility Name

Novartis Investigative Site

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H3T 1C5

Country

Canada

Facility Name

Novartis Investigative Site

City

Paris 10

State/Province

Cedex 10

ZIP/Postal Code

75475

Country

France

Facility Name

Novartis Investigative Site

City

Paris

ZIP/Postal Code

75019

Country

France

Facility Name

Novartis Investigative Site

City

Frankfurt

ZIP/Postal Code

60590

Country

Germany

Facility Name

Novartis Investigative Site

City

Monza

State/Province

ZIP/Postal Code

20900

Country

Italy

Facility Name

Novartis Investigative Site

City

Kyoto

ZIP/Postal Code

606 8507

Country

Japan

Facility Name

Novartis Investigative Site

City

Oslo

ZIP/Postal Code

0424

Country

Norway

Facility Name

Novartis Investigative Site

City

Esplugues De Llobregat

State/Province

Barcelona

ZIP/Postal Code

08950

Country

Spain

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

IPD Sharing URL

https://www.clinicalstudydatarequest.com

Citations:

PubMed Identifier

36399695

Citation

Laetsch TW, Maude SL, Rives S, Hiramatsu H, Bittencourt H, Bader P, Baruchel A, Boyer M, De Moerloose B, Qayed M, Buechner J, Pulsipher MA, Myers GD, Stefanski HE, Martin PL, Nemecek E, Peters C, Yanik G, Khaw SL, Davis KL, Krueger J, Balduzzi A, Boissel N, Tiwari R, O'Donovan D, Grupp SA. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial. J Clin Oncol. 2023 Mar 20;41(9):1664-1669. doi: 10.1200/JCO.22.00642. Epub 2022 Nov 18.

Results Reference

derived

PubMed Identifier

36351239

Citation

Newman H, Li Y, Liu H, Myers RM, Tam V, DiNofia A, Wray L, Rheingold SR, Callahan C, White C, Baniewicz D, Winestone LE, Kadauke S, Diorio C, June CH, Getz KD, Aplenc R, Teachey DT, Maude SL, Grupp SA, Bona K, Leahy AB. Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy. Blood. 2023 Feb 9;141(6):609-619. doi: 10.1182/blood.2022017866.

Results Reference

derived

PubMed Identifier

35422096

Citation

Laetsch TW, Maude SL, Balduzzi A, Rives S, Bittencourt H, Boyer MW, Buechner J, De Moerloose B, Qayed M, Phillips CL, Pulsipher MA, Hiramatsu H, Tiwari R, Grupp SA. Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2022 Jun;36(6):1508-1515. doi: 10.1038/s41375-022-01550-z. Epub 2022 Apr 14.

Results Reference

derived

PubMed Identifier

34432863

Citation

Thudium Mueller K, Grupp SA, Maude SL, Levine JE, Pulsipher MA, Boyer MW, August KJ, Myers GD, Tam CS, Jaeger U, Foley SR, Borchmann P, Schuster SJ, Waller EK, Awasthi R, Potthoff B, Warren A, Waldron ER, McBlane F, Chassot-Agostinho A, Laetsch TW. Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Blood Adv. 2021 Dec 14;5(23):4980-4991. doi: 10.1182/bloodadvances.2020003844.

Results Reference

derived

PubMed Identifier

34353848

Citation

Levine JE, Grupp SA, Pulsipher MA, Dietz AC, Rives S, Myers GD, August KJ, Verneris MR, Buechner J, Laetsch TW, Bittencourt H, Baruchel A, Boyer MW, De Moerloose B, Qayed M, Davies SM, Phillips CL, Driscoll TA, Bader P, Schlis K, Wood PA, Mody R, Yi L, Leung M, Eldjerou LK, June CH, Maude SL. Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia. J Immunother Cancer. 2021 Aug;9(8):e002287. doi: 10.1136/jitc-2020-002287.

Results Reference

derived

PubMed Identifier

33496754

Citation

Buechner J, Grupp SA, Hiramatsu H, Teachey DT, Rives S, Laetsch TW, Yanik GA, Wood P, Awasthi R, Yi L, Chassot-Agostinho A, Eldjerou LK, De Moerloose B. Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy. Blood Adv. 2021 Jan 26;5(2):593-601. doi: 10.1182/bloodadvances.2020002757.

Results Reference

derived

PubMed Identifier

31606419

Citation

Laetsch TW, Myers GD, Baruchel A, Dietz AC, Pulsipher MA, Bittencourt H, Buechner J, De Moerloose B, Davis KL, Nemecek E, Driscoll T, Mechinaud F, Boissel N, Rives S, Bader P, Peters C, Sabnis HS, Grupp SA, Yanik GA, Hiramatsu H, Stefanski HE, Rasouliyan L, Yi L, Shah S, Zhang J, Harris AC. Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial. Lancet Oncol. 2019 Dec;20(12):1710-1718. doi: 10.1016/S1470-2045(19)30493-0. Epub 2019 Oct 9.

Results Reference

derived

PubMed Identifier

29385370

Citation

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. doi: 10.1056/NEJMoa1709866.

Results Reference

derived

Learn more about this trial

Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

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