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

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ClinicalTrials.gov Identifier: NCT03876769
Recruitment Status : Recruiting
First Posted : March 15, 2019
Last Update Posted : November 28, 2019
Sponsor:
Collaborator:
Children's Oncology Group
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
B-Cell Acute Lymphoblastic Leukemia Biological: CTL019 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : June 24, 2019
Estimated Primary Completion Date : November 26, 2026
Estimated Study Completion Date : August 26, 2027


Arm Intervention/treatment
Experimental: Single dose of CTL019

Based 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

Biological: CTL019

Based 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





Primary Outcome Measures :
  1. Disease Free Survival (DFS) rate [ Time Frame: 5 years after tisagenlecleucel infusion ]
    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 :
  1. Percentage of participants who are disease free without allogeneic stem cell transplant (SCT) [ Time Frame: 12 months after last infusion ]
    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.

  2. Overall Survival [ Time Frame: 8 years ]
    Time from tisagenlecleucel infusion to the death due to any cause

  3. Percentage of participants achieving MRD negative CR or CRi at Month 3 [ Time Frame: 3 months after the tisagenlecleucel infusion. ]
    MRD negative status as determined by central laboratory using multi-parameter flow cytometry

  4. Percentage of participants with in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion [ Time Frame: 8 years ]
    Absolute lymphocyte CD19 count of >50/uL

  5. 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 ]
    Success in manufacturing of tisagenlecleucel dose for patients who are ≥1 year and <3 years as respective time points.

  6. Pediatric Quality of Life (PedsQL) [ Time Frame: 5 years ]

    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).


  7. European Quality of Life 5 dimensions (EQ-5D-3L & EQ-5D-Y)) [ Time Frame: 5 years ]

    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).


  8. Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Detection test [ Time Frame: 5 years ]
    Speed of performance (mean of the log10 transformed reaction times for correct responses)

  9. Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: Identification test [ Time Frame: 5 years ]
    This test measures the speed of performance (mean of the log10 transformed reaction times for correct responses)

  10. Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Groton Maze Learning test [ Time Frame: 5 years ]
    This test looks at the total number of errors made in attempting to learn the hidden pathways during a single session.

  11. Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: One Back test [ Time Frame: 5 years ]
    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).

  12. Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: One card learning test [ Time Frame: 5 years ]
    This test measures the accuracy of performance (arcsine transformation of the square root of the proportion of correct responses).

  13. Percentage of participants with pre-existing antibodies [ Time Frame: 8 years ]
    Prevalence of immunogenicity

  14. Percentage of participants with anti-m CAR19 antibodies post infusion with tisagenlecleucel and % of patients without measureable anti-mCAR19 antibodies [ Time Frame: 8 years ]
    Incidence of immunogenicity

  15. 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 ]
    Impact of immunogenicity on clinical response

  16. tisagenlecleucel transgene concentration [ Time Frame: 8 years ]
    Transgene concentration as detected by qPCR in target tissue

  17. Expression of tisagenlecleucel [ Time Frame: 8 years ]
    Summary of tisagenlecleucel CAR-positive viable T cells measured by flow cytometry in target tissue

  18. 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 ]
    Relationship between B-cell recovery and transgene levels

  19. Cmax; cellular kinetic parameter of tisagenlecleucel [ Time Frame: 8 years ]
    The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/μg)

  20. Tmax; cellular kinetic parameter of tisagenlecleucel [ Time Frame: 8 years ]
    The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days)

  21. AUC0-29d and 84d; cellular kinetic parameter of tisagenlecleucel [ Time Frame: 8 years ]
    The AUC from time zero to day 29 and 84 or other disease assessment days, in peripheral blood (% or copies/μg x days )

  22. AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel [ Time Frame: 8 years ]
    The AUC from time zero to Tmax in peripheral blood (% or copies/μg x days)

  23. T1/2; cellular kinetic parameter of tisagenlecleucel [ Time Frame: 8 years ]
    The half-life associated with the elimination phase slope of a semi logarithmic concentration-time curve (days) in peripheral blood

  24. Clast; cellular kinetic parameter of tisagenlecleucel [ Time Frame: 8 years ]
    The last observed quantifiable concentration in peripheral blood (% or copies/μg)

  25. Tlast; cellular kinetic parameter of tisagenlecleucel [ Time Frame: 8 years ]
    The time of last observed quantifiable concentration in peripheral blood (days)

  26. Impact of tisagenlecleucel dose on day 29 response [ Time Frame: 8 years ]
    Clinical response summarized by quartile of administered doses

  27. AUC 0 - 29d; cellular kinetic parameter of tisagenlecleucel [ Time Frame: Day 29 ]
    Impact of tisagenlecleucel exposure on day 29 response; The AUC from time zero to day 29 in peripheral blood (% or copies/μg x days )

  28. Cmax: cellular kinetic parameter of tisagenlecleucel [ Time Frame: Day 29 ]
    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)

  29. Tmax: cellular kinetic parameter of tisagenlecleucel [ Time Frame: Day 29 ]
    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)

  30. T1/2: cellular kinetic parameter of tisagenlecleucel [ Time Frame: Day 29 ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03876769


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

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Sponsors and Collaborators
Novartis Pharmaceuticals
Children's Oncology Group
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03876769     History of Changes
Other Study ID Numbers: CCTL019G2201J
2017-002116-14 ( EudraCT Number )
First Posted: March 15, 2019    Key Record Dates
Last Update Posted: November 28, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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 expert 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 is currently available according to the process described on www.clinicalstudydatarequest.com.


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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)
Additional relevant MeSH terms:
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Burkitt Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Lymphoma