Clinical Trials /

Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients

NCT03876769

Description:

This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of tisagenlecleucel in de novo HR pediatric and young adult B-ALL patients who received first-line treatment and are EOC MRD positive. The study will have the following sequential phases: screening, pre-treatment, treatment & follow-up, and survival. After tisagenlecleucel infusion, efficacy will be assessed at Day 29, then every 3 months for the first year, every 6 months for the second year, then yearly until the end of the study. Safety will be assessed throughout the study. The study is expected to end in approximately 8 years after first patient first treatment (FPFT). A post-study long term follow-up for lentiviral vector safety will continue under a separate protocol per health authority guidelines.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients
  • Official Title: A Phase II Trial of Tisagenlecleucel in First-line High-risk (HR) Pediatric and Young Adult Patients With B-cell Acute Lymphoblastic Leukemia (B-ALL) Who Are Minimal Residual Disease (MRD) Positive at the End of Consolidation (EOC) Therapy

Clinical Trial IDs

  • ORG STUDY ID: CCTL019G2201J
  • NCT ID: NCT03876769

Conditions

  • B-Cell Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
CTL019Single dose of CTL019

Purpose

This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of tisagenlecleucel in de novo HR pediatric and young adult B-ALL patients who received first-line treatment and are EOC MRD positive. The study will have the following sequential phases: screening, pre-treatment, treatment & follow-up, and survival. After tisagenlecleucel infusion, efficacy will be assessed at Day 29, then every 3 months for the first year, every 6 months for the second year, then yearly until the end of the study. Safety will be assessed throughout the study. The study is expected to end in approximately 8 years after first patient first treatment (FPFT). A post-study long term follow-up for lentiviral vector safety will continue under a separate protocol per health authority guidelines.

Trial Arms

NameTypeDescriptionInterventions
Single dose of CTL019ExperimentalBased on the subject's weight one of two possible dose ranges will be prepared for the subject: Subjects ≤ 50 kg: 0.2 to 5.0 x 10(6) CAR-positive viable T cells per kg body weight OR Subjects > 50 kg: 0.1 to 2.5 x 10(8) CAR-positive viable T cells
  • CTL019

Eligibility Criteria

        Inclusion Criteria:

          1. CD19 expressing B-cell Acute Lymphoblastic Leukemia

          2. De novo NCI HR B-ALL who received first-line treatment and are MRD ≥ 0.01% at EOC. EOC
             bone marrow MRD will be collected prior to screening and will be assessed by
             multi-parameter flow cytometry using central laboratory analysis.

          3. Age 1 to 25 years at the time of screening

          4. Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60%

          5. Adequate organ function during the screening period:

             A. Renal function based on age/gender B. ALT ≤ 5 times ULN for age C. AST ≤ 5 times
             ULN for age D. Total bilirubin < 2 mg/dL (for Gilbert's Syndrome subjects total
             bilirubin < 4 mg/dL)

             E. Adequate pulmonary function defined as:

               -  no or mild dyspnea (≤ Grade 1)

               -  oxygen saturation of > 90% on room air F. Adequate cardiac function defined as
                  LVSF ≥ 28% confirmed by echocardiogram or LVEF ≥ 45% confirmed by echocardiogram
                  or MUGA within 6 weeks of screening

          6. Prior induction and consolidation chemotherapy allowed: 1st line subjects: ≤ 3 blocks
             of standard chemotherapy for first-line B-ALL, defined as 4-drug induction, augmented
             Berlin-Frankfurt-Münster (BFM) consolidation, and interim maintenance with high-dose
             methotrexate.

        Exclusion Criteria:

          1. M3 marrow at the completion of 1st line induction therapy

          2. M2 or M3 marrow or persistent extramedullary disease at the completion of first-line
             consolidation therapy. Patients with previous CNS disease are eligible if there is no
             active CNS involvement of leukemia at the time of enrollment.

          3. Philadelphia chromosome positive ALL

          4. Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence
             of a hypodiploid clone

          5. Prior tyrosine kinase inhibitor therapy

          6. Subjects with concomitant genetic syndromes associated with bone marrow failure
             states: such as subjects with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or
             any other known bone marrow failure syndrome. Subjects with Down syndrome will not be
             excluded.

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

          8. Has had treatment with any prior anti-CD19 therapy 9. Treatment with any prior gene or
             engineered T cell therapy

        Other protocol-defined inclusion/exclusion may apply.
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease Free Survival (DFS) rate
Time Frame:5 years after tisagenlecleucel infusion
Safety Issue:
Description:DFS is defined as the time from the date of tisagenlecleucel infusion to the date of the first documented morphological relapse, occurrence of secondary malignancy or death due to any cause.

Secondary Outcome Measures

Measure:Percentage of participants who are disease free without allogeneic stem cell transplant (SCT)
Time Frame:12 months after last infusion
Safety Issue:
Description:Minimal Residual Disease (MRD) negative remission (complete remission (CR) or Complete remission with incomplete blood count recovery CRi)) at Month 12 without SCT after tisagenlecleucel infusion.
Measure:Overall Survival
Time Frame:8 years
Safety Issue:
Description:Time from tisagenlecleucel infusion to the death due to any cause
Measure:Percentage of participants achieving MRD negative CR or CRi at Month 3
Time Frame:3 months after the tisagenlecleucel infusion.
Safety Issue:
Description:MRD negative status as determined by central laboratory using multi-parameter flow cytometry
Measure:Percentage of participants with in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion
Time Frame:8 years
Safety Issue:
Description:Absolute lymphocyte CD19 count of >50/uL
Measure:Percentage of participants who have tisagenlecleucel product successfully manufactured over the total number of subjects enrolled for the age ≥1 year and < 3 years
Time Frame:8 years
Safety Issue:
Description:Success in manufacturing of tisagenlecleucel dose for patients who are ≥1 year and <3 years as respective time points.
Measure:Pediatric Quality of Life (PedsQL)
Time Frame:5 years
Safety Issue:
Description:Patient reported outcome to assess quality of life in patients aged 8 and above. The 23 items PedQL (Pediatrics Quality of Life Inventory) measure core dimensions of health as delineated by the World Health Organization, as well as role (school) functioning. Items measured include 1) Physical Functioning (8 items), 2) Emotional Functioning (5 items), 3) Social Functioning (5 items), and 4) School Functioning (5 items). Each item is measured on a 5 point Likert scale with 0 indicating "never" and 4 indicating "almost always". The Likert scores are reversed scored and linearly transform to a 0-100 scale with 0=100, 1-75, 2=50, 5=25, and 4=0. A higher score indicates better health-related quality of life (HRQoL).
Measure:European Quality of Life 5 dimensions (EQ-5D-3L & EQ-5D-Y))
Time Frame:5 years
Safety Issue:
Description:Patient reported outcome to assess health status in patients aged 8 and above. The EQ-5D (European Quality of Life -5 Dimensions) measures a wide range of health conditions and treatments; it is composed of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and a visual analogue scale (EQ-visual analogue scale [EQ-VAS]) that records the patient's self-rated overall health state. Respondents rate each of these 5 dimensions from "no problem", "some problem," or "extreme problem". The EQ-VAS records the respondents' self-related health on a vertical, visual analogue scale. The range for EQ-VAS is from 0 (=the worst health you can imagine) to 100 (=the best health you can imagine).
Measure:Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Detection test
Time Frame:5 years
Safety Issue:
Description:Speed of performance (mean of the log10 transformed reaction times for correct responses)
Measure:Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: Identification test
Time Frame:5 years
Safety Issue:
Description:This test measures the speed of performance (mean of the log10 transformed reaction times for correct responses)
Measure:Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Groton Maze Learning test
Time Frame:5 years
Safety Issue:
Description:This test looks at the total number of errors made in attempting to learn the hidden pathways during a single session.
Measure:Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: One Back test
Time Frame:5 years
Safety Issue:
Description:This test measures the accuracy of performance (arcsine transformation of the square root of the percentage of correct responses). The test also measures the speed of performance (mean of the log10 transformed reaction times for correct responses).
Measure:Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: One card learning test
Time Frame:5 years
Safety Issue:
Description:This test measures the accuracy of performance (arcsine transformation of the square root of the proportion of correct responses).
Measure:Percentage of participants with pre-existing antibodies
Time Frame:8 years
Safety Issue:
Description:Prevalence of immunogenicity
Measure:Percentage of participants with anti-m CAR19 antibodies post infusion with tisagenlecleucel and % of patients without measureable anti-mCAR19 antibodies
Time Frame:8 years
Safety Issue:
Description:Incidence of immunogenicity
Measure:Percentage of patients that have measureable anti-mCAR19 antibodies above patient specific cut-point (reported as a %) pre and post tisagenlecleucel infusion categorized by Day 28 response
Time Frame:8 years
Safety Issue:
Description:Impact of immunogenicity on clinical response
Measure:tisagenlecleucel transgene concentration
Time Frame:8 years
Safety Issue:
Description:Transgene concentration as detected by qPCR in target tissue
Measure:Expression of tisagenlecleucel
Time Frame:8 years
Safety Issue:
Description:Summary of tisagenlecleucel CAR-positive viable T cells measured by flow cytometry in target tissue
Measure:Persistence of CAR (reported as copies/ug) categorized by the time to B-cell recovery (recovery < 3 months, >3 months to < 6months, > 6 months)
Time Frame:8 years
Safety Issue:
Description:Relationship between B-cell recovery and transgene levels
Measure:Cmax; cellular kinetic parameter of tisagenlecleucel
Time Frame:8 years
Safety Issue:
Description:The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/μg)
Measure:Tmax; cellular kinetic parameter of tisagenlecleucel
Time Frame:8 years
Safety Issue:
Description:The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days)
Measure:AUC0-29d and 84d; cellular kinetic parameter of tisagenlecleucel
Time Frame:8 years
Safety Issue:
Description:The AUC from time zero to day 29 and 84 or other disease assessment days, in peripheral blood (% or copies/μg x days )
Measure:AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel
Time Frame:8 years
Safety Issue:
Description:The AUC from time zero to Tmax in peripheral blood (% or copies/μg x days)
Measure:T1/2; cellular kinetic parameter of tisagenlecleucel
Time Frame:8 years
Safety Issue:
Description:The half-life associated with the elimination phase slope of a semi logarithmic concentration-time curve (days) in peripheral blood
Measure:Clast; cellular kinetic parameter of tisagenlecleucel
Time Frame:8 years
Safety Issue:
Description:The last observed quantifiable concentration in peripheral blood (% or copies/μg)
Measure:Tlast; cellular kinetic parameter of tisagenlecleucel
Time Frame:8 years
Safety Issue:
Description:The time of last observed quantifiable concentration in peripheral blood (days)
Measure:Impact of tisagenlecleucel dose on day 29 response
Time Frame:8 years
Safety Issue:
Description:Clinical response summarized by quartile of administered doses
Measure:AUC 0 - 29d; cellular kinetic parameter of tisagenlecleucel
Time Frame:Day 29
Safety Issue:
Description:Impact of tisagenlecleucel exposure on day 29 response; The AUC from time zero to day 29 in peripheral blood (% or copies/μg x days )
Measure:Cmax: cellular kinetic parameter of tisagenlecleucel
Time Frame:Day 29
Safety Issue:
Description:Impact of tisagenlecleucel exposure on day 29 response; The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/μg)
Measure:Tmax: cellular kinetic parameter of tisagenlecleucel
Time Frame:Day 29
Safety Issue:
Description:Impact of tisagenlecleucel exposure on day 29 response; The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days)
Measure:T1/2: cellular kinetic parameter of tisagenlecleucel
Time Frame:Day 29
Safety Issue:
Description:Impact of tisagenlecleucel exposure on day 29 response; The half-life associated with the elimination phase slope of a semi logarithmic concentration-time curve (days) in peripheral blood

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • CTL019
  • Kymriah
  • B-Cell Acute Lymphoblastic Leukemia
  • ALL
  • tisagenlecleucel
  • HR B-ALL EOC MRD
  • Minimal Residual Disease (MRD)
  • Positive at the End of Consolidation (EOC)

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