Clinical trial NCT02435849: Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-05-06
Enrollment: 80
Sex: ALL
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Overall Remission Rate (ORR) as Determined by Independent Review Committee (IRC) Assessment.
timeFrame: during the 3 months after tisagenlecleucel administration
Secondary outcomes:
measure: Percentage of Participants With Overall Remission Rate (ORR) as Per IRC From US Manufacturing Facilities in the Main Cohort Only (Key Secondary)
timeFrame: 3 months after tisagenlecleucel administration
measure: 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)
timeFrame: 3 months after tisagenlecleucel administration
measure: 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)
timeFrame: 3 months after tisagenlecleucel administration
measure: Percentage of Participants Who Achieved CR or CRi Without Hematopoietic Stem Cell Transplantation (HSCT)
timeFrame: 6 months after tisagenlecleucel administration
measure: 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
timeFrame: 6 months
measure: Number of Participants Who Proceeded to Hematopoietic Stem Cell Transplantation (HSCT) After Tisagenlecleucel (CTL019) Infusion
timeFrame: up to 6 months
measure: Duration of Remission (DOR)
timeFrame: 60 months
measure: Site of Involvement of Subsequent Relapse
timeFrame: 60 months
measure: Relapse-free Survival Per IRC Assessment
timeFrame: 60 months
measure: Event-free Survival Per IRC Assessment
timeFrame: 60 months
measure: Overall Survival (OS)
timeFrame: 60 months
measure: Percentage of Participants Attaining CR or CRi at Day 28 +/- 4 Days Post Tisagenlecleucel (CTL019) Infusion by IRC Assessment
timeFrame: 1 month
measure: Response as a Function of Baseline Tumor Burden (Tumor Load) in Main Cohort Only
timeFrame: 3 months
measure: Bone Marrow MRD Status by Flow Cytometry Per IRC Assessment
timeFrame: 28 days
measure: Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood by Day 28 Response by Independent Review Committee (IRC) Assessment
timeFrame: Month 60
measure: Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow by Day 28 Response by IRC Assessment
timeFrame: Month 6
measure: Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Peripheral Blood by Day 28 Disease Response Per IRC Assessment
timeFrame: Month 60
measure: Expression of Tisagenlecleucel (CTL019) Detected by Flow Cytometry in Bone Marrow by Day 28 Response by IRC Assessment
timeFrame: Month 6
measure: Pharmacokinetics (PK) Parameter: Cmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC
timeFrame: 60 months
measure: Pharmacokinetics (PK) Parameter: Tmax by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC
timeFrame: 60 months
measure: Pharmacokinetics (PK) Parameter: AUCs by qPCR in Peripheral Blood, by Day 28 Disease Response by IRC
timeFrame: 0 to 84 days after infusion
measure: Persistence of Tisagenlecleucel (CTL019) in Blood, Bone Marrow and CSF if Available, by qPCR, by Day 28 Response by IRC
timeFrame: 60 months
measure: Prevalence and Incidence of Immunogenicity to Tisagenlecleucel (CTL019)
timeFrame: At any time post-baseline, up to a max. of 60 months
measure: Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by PedsQL Questionnaire
timeFrame: Month 3, M6, M12, M24, M60
measure: Effects of CTL019 Therapy on Patient Reported Outcomes as Measured by EQ-5D Questionnaire
timeFrame: Month 60
measure: Develop a Score Utilizing Clinical and Biomarker Data and Assess Its Ability for Early Prediction of Cytokine Release Syndrome (CRS)
timeFrame: 3 months
measure: Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (C Reactive Protein & Ferritin)
timeFrame: Maximum post-baseline (approx. 60 months)
measure: Frequent Monitoring of Concentrations of Soluble Immune Factors in Blood (All Other Inflammatory Markers)
timeFrame: Maximum post-baseline (approx. 60 months)
measure: Percentage Change From Baseline of Levels of B and T Cells (Blood and Bone Marrow) Prior to and Following CTL019 Infusion
timeFrame: Month 3, Month 12, Maximum post-baseline (approx. 60 months)
measure: Percentage of Participants With Overall Remission Rate (ORR) - From Fraunhofer Institute Manufacturing Facility
timeFrame: 60 months
measure: 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
timeFrame: 3 months
measure: Tisagenlecleucel Transgene Levels by qPCR in Peripheral Blood - Tisagenlecleucel Manufactured From Fraunhofer Institute
timeFrame: Month 60
measure: Tisagenlecleucel Transgene Levels by qPCR in Bone Marrow - Tisagenlecleucel Manufactured From Fraunhofer Institute
timeFrame: Month 3
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles SC CTL019
state: California
city: Stanford
country: United States
facility: Stanford Universtiy Medical Center SC - CTL019B2205J - B2206
state: California
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta SC CTL019
state: Georgia
city: Ann Arbor
country: United States
facility: University of Michigan .
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Kansas City
country: United States
facility: Children s Mercy Hospital SC - CTL019B2205J
state: Missouri
city: Durham
country: United States
facility: Duke Unversity Medical Center .
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University Doernbecher Children's Hosp.
state: Oregon
city: Philadelphia
country: United States
facility: The Childrens Hospital of Philadelphia CHOP
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center .
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Clinical Trials Office SC - CTL019B2205J
state: Utah
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Paris 10
country: France
facility: Novartis Investigative Site
state: Cedex 10
city: Paris
country: France
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Kyoto
country: Japan
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Esplugues De Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
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