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

Study Overview
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Brief Summary
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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, patient will have assessments performed more frequently in the first month and then 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. Efficacy and safety will be assessed at study visits and as clinically indicated 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 safety will continue under a separate protocol per health authority guidelines.

Official Title
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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

Conditions
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B-Cell Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: CTL019


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CD19 expressing B-cell Acute Lymphoblastic Leukemia 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. Age 1 to 25 years at the time of screening Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60% 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 Prior induction and consolidation chemotherapy allowed: 1st line subjects: ≤ 3 blocks of standard chemotherapy for first-line B-ALL, defined as 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation or Phase 1b, and interim maintenance with high-dose methotrexate. Exclusion Criteria: M3 marrow at the completion of 1st line induction therapy M2 or M3 marrow or persistent extramedullary disease at the completion of first-line consolidation therapy or evidence of disease progression in the peripheral blood or new extramedullary disease prior to enrollment. Patients with previous CNS disease are eligible if there is no active CNS involvement of leukemia at the time of screening. Philadelphia chromosome positive ALL Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a hypodiploid clone Prior tyrosine kinase inhibitor therapy 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. 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) 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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single dose of CTL019<br>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<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) rate without censoring for new anticancer therapy, including Stem Cell Transplantation (SCT) while in remission | 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. | 5 years after tisagenlecleucel infusion | 
| Overall Survival (OS) rate | OS is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any reason. | 4 years after tisagenlecleucel | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who are disease free without allogeneic stem cell transplant (SCT) | 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. | 12 months after last infusion | 
| DFS rate with censoring for new anticancer therapy, including SCT, while in remission | Assessing the effect of tisagenlecleucel on DFS if new anticancer therapy is not available. | 5 years | 
| Percentage of participants achieving MRD negative CR or CRi at Month 3 | Assessing the percentage of participants who achieved MRD negative complete response (CR) or Complete remission with incomplete blood count recovery (CRi) status as determined by central laboratory using multi-parameter flow cytometry. | 3 months after the tisagenlecleucel infusion. | 
| Percentage of participants with in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion | Absolute lymphocyte CD19 count of <50/uL | 8 years | 
| Percentage of participants who have tisagenlecleucel product successfully manufactured over the total number of subjects enrolled for the age ≥1 year and < 3 years | Success in manufacturing of tisagenlecleucel dose for patients who are ≥1 year and <3 years as respective time points. | 8 years | 
| Pediatric Quality of Life (PedsQL) | 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). | 5 years | 
| European Quality of Life 5 dimensions (EQ-5D-3L & EQ-5D-Y)) | 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). | 5 years | 
| Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Detection test | Speed of performance (mean of the log10 transformed reaction times for correct responses) | 5 years | 
| Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: Identification test | This test measures the speed of performance (mean of the log10 transformed reaction times for correct responses) | 5 years | 
| Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Groton Maze Learning test | This test looks at the total number of errors made in attempting to learn the hidden pathways during a single session. | 5 years | 
| Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: One Back test | 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). | 5 years | 
| Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: One card learning test | This test measures the accuracy of performance (arcsine transformation of the square root of the proportion of correct responses). | 5 years | 
| Percentage of participants with pre-existing antibodies | Prevalence of immunogenicity | 8 years | 
| Percentage of participants with anti-m CAR19 antibodies post infusion with tisagenlecleucel and % of patients without measureable anti-mCAR19 antibodies | Incidence of immunogenicity | 8 years | 
| 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 | Impact of immunogenicity on clinical response | 8 years | 
| tisagenlecleucel transgene concentration | Transgene concentration as detected by qPCR in target tissue | 8 years | 
| Expression of tisagenlecleucel | Summary of tisagenlecleucel CAR-positive viable T cells measured by flow cytometry in target tissue | 8 years | 
| Persistence of CAR (reported as copies/ug) categorized by the time to B-cell recovery (recovery < 3 months, >3 months to < 6months, > 6 months) | Relationship between B-cell recovery and transgene levels | 8 years | 
| Cmax; cellular kinetic parameter of tisagenlecleucel | The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/μg) | 8 years | 
| Tmax; cellular kinetic parameter of tisagenlecleucel | The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days) | 8 years | 
| AUC0-29d and 84d; cellular kinetic parameter of tisagenlecleucel | The AUC from time zero to day 29 and 84 or other disease assessment days, in peripheral blood (% or copies/μg x days ) | 8 years | 
| AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel | The AUC from time zero to Tmax in peripheral blood (% or copies/μg x days) | 8 years | 
| T1/2; cellular kinetic parameter of tisagenlecleucel | The half-life associated with the elimination phase slope of a semi logarithmic concentration-time curve (days) in peripheral blood | 8 years | 
| Clast; cellular kinetic parameter of tisagenlecleucel | The last observed quantifiable concentration in peripheral blood (% or copies/μg) | 8 years | 
| Tlast; cellular kinetic parameter of tisagenlecleucel | The time of last observed quantifiable concentration in peripheral blood (days) | 8 years | 
| Impact of tisagenlecleucel dose on day 29 response | Clinical response summarized by quartile of administered doses | 8 years | 
| AUC 0 - 29d; cellular kinetic parameter of tisagenlecleucel | Impact of tisagenlecleucel exposure on day 29 response; The AUC from time zero to day 29 in peripheral blood (% or copies/μg x days ) | Day 29 | 
| Cmax: cellular kinetic parameter of tisagenlecleucel | 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) | Day 29 | 
| Tmax: cellular kinetic parameter of tisagenlecleucel | 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) | Day 29 | 
| T1/2: cellular kinetic parameter of tisagenlecleucel | 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 | Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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)