Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

B-cell Acute Lymphoblastic Leukemia Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02435849
• Other study ID #: CCTL019B2202
• Secondary ID: 2013-003205-25
• Status: Completed
• Phase: Phase 2
• Start date: April 8, 2015
• Est. completion date: November 17, 2022

Study information

• Verified date: December 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: November 17, 2022
• Est. primary completion date: January 21, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 25 Years

Eligibility

Inclusion Criteria:

1. Relapsed or refractory pediatric B-cell ALL

2. Adequate organ function

3. For relapsed patients, documentation of CD19 tumor expression within 3 months of study entry.

4. Bone marrow with = 5% lymphoblasts by morphologic assessment at screening.

5. Life expectancy > 12 weeks.

6. Karnofsky (age =16 years) or Lansky (age < 16 years) performance status = 50 at screening

7. Signed written informed consent and assent forms

8. Must meet the institutional criteria to undergo leukapheresis or have an acceptable, store leukapheresis product

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

10. Cohort 1 only:

1. First relapse AND hypodiploid cytogenetics OR

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

3. 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

1. Isolated extra-medullary disease relapse

2. 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.

3. 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)

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

5. Treatment with any prior gene therapy product

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

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

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

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

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

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

12. Pregnant or nursing (lactating) women.

13. 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

14. 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

Related Conditions & MeSH terms

• B-cell Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Biological:
• CTL019
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).

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Parkville	Victoria
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Gent
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris 10	Cedex 10
Germany	Novartis Investigative Site	Frankfurt
Italy	Novartis Investigative Site	Monza	MB
Japan	Novartis Investigative Site	Kyoto
Norway	Novartis Investigative Site	Oslo
Spain	Novartis Investigative Site	Esplugues De Llobregat	Barcelona
United States	University of Michigan .	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta SC CTL019	Atlanta	Georgia
United States	University of Texas Southwestern Medical Center .	Dallas	Texas
United States	Duke Unversity Medical Center .	Durham	North Carolina
United States	Children s Mercy Hospital SC - CTL019B2205J	Kansas City	Missouri
United States	Childrens Hospital Los Angeles SC CTL019	Los Angeles	California
United States	University of Minnesota	Minneapolis	Minnesota
United States	The Childrens Hospital of Philadelphia CHOP	Philadelphia	Pennsylvania
United States	Oregon Health and Science University Doernbecher Children's Hosp.	Portland	Oregon
United States	University of Utah Clinical Trials Office SC - CTL019B2205J	Salt Lake City	Utah
United States	Stanford Universtiy Medical Center SC - CTL019B2205J - B2206	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  France,  Germany,  Italy,  Japan,  Norway,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	during the 3 months after tisagenlecleucel administration
Secondary	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.	3 months after tisagenlecleucel administration
Secondary	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.	3 months after tisagenlecleucel administration
Secondary	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%	3 months after tisagenlecleucel administration
Secondary	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.	6 months after tisagenlecleucel administration
Secondary	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	6 months
Secondary	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.	up to 6 months
Secondary	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.	60 months
Secondary	Site of Involvement of Subsequent Relapse	Anatomical location of relapse in participants who achieved prior CR/CRi subsequent to tisagenlecleucel infusion.	60 months
Secondary	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.	60 months
Secondary	Event-free Survival Per IRC Assessment	EFS is the time from date of tisagenlecleucel infusion to the earliest of death, relapse or treatment failure.	60 months
Secondary	Overall Survival (OS)	OS, is the time from date of tisagenlecleucel infusion to the date of death due to any reason.	60 months
Secondary	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.	1 month
Secondary	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.	3 months
Secondary	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.	28 days
Secondary	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.	Month 60
Secondary	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.	Month 6
Secondary	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.	Month 60
Secondary	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.	Month 6
Secondary	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.	60 months
Secondary	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.	60 months
Secondary	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).	0 to 84 days after infusion
Secondary	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.	60 months
Secondary	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. .	At any time post-baseline, up to a max. of 60 months
Secondary	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).	Month 3, M6, M12, M24, M60
Secondary	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.	Month 60
Secondary	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.	3 months
Secondary	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).	Maximum post-baseline (approx. 60 months)
Secondary	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).	Maximum post-baseline (approx. 60 months)
Secondary	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	Month 3, Month 12, Maximum post-baseline (approx. 60 months)
Secondary	Percentage of Participants With Overall Remission Rate (ORR) - From Fraunhofer Institute Manufacturing Facility	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 Fraunhofer Institute manufacturing facility.	60 months
Secondary	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.	3 months
Secondary	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.	Month 60
Secondary	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.	Month 3