Study of Efficacy and Safety of Tisagenlecleucel in HR B-ALL EOC MRD Positive Patients
- Conditions
- B-Cell Acute Lymphoblastic Leukemia
- Interventions
- Biological: CTL019
- Registration Number
- NCT03876769
- Lead Sponsor
- 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, 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 121
-
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
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Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60%
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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
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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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Single dose of CTL019 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
Name Time Method Disease Free Survival (DFS) rate without censoring for new anticancer therapy, including Stem Cell Transplantation (SCT) while in remission 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.
Overall Survival (OS) rate 4 years after tisagenlecleucel OS is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any reason.
- Secondary Outcome Measures
Name Time Method Percentage of participants with pre-existing antibodies 8 years Prevalence of immunogenicity
Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Groton Maze Learning test 5 years This test looks at the total number of errors made in attempting to learn the hidden pathways during a single session.
Percentage of participants with anti-m CAR19 antibodies post infusion with tisagenlecleucel and % of patients without measureable anti-mCAR19 antibodies 8 years Incidence of immunogenicity
Expression of tisagenlecleucel 8 years Summary of tisagenlecleucel CAR-positive viable T cells measured by flow cytometry in target tissue
AUC0-29d and 84d; cellular kinetic parameter of tisagenlecleucel 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 )
Impact of tisagenlecleucel dose on day 29 response 8 years Clinical response summarized by quartile of administered doses
Percentage of participants who are disease free without allogeneic stem cell transplant (SCT) 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.
DFS rate with censoring for new anticancer therapy, including SCT, while in remission 5 years Assessing the effect of tisagenlecleucel on DFS if new anticancer therapy is not available.
Percentage of participants who have tisagenlecleucel product successfully manufactured over the total number of subjects enrolled for the age ≥1 year and < 3 years 8 years Success in manufacturing of tisagenlecleucel dose for patients who are ≥1 year and \<3 years as respective time points.
Pediatric Quality of Life (PedsQL) 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).Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Detection test 5 years Speed of performance (mean of the log10 transformed reaction times for correct responses)
Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: Identification test 5 years This test measures the speed of performance (mean of the log10 transformed reaction times for correct responses)
Percentage of participants achieving MRD negative CR or CRi at Month 3 3 months after the tisagenlecleucel infusion. 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.
Percentage of participants with in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion 8 years Absolute lymphocyte CD19 count of \<50/uL
Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: One Back test 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).
Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: One card learning test 5 years This test measures the accuracy of performance (arcsine transformation of the square root of the proportion of correct responses).
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 8 years Impact of immunogenicity on clinical response
Persistence of CAR (reported as copies/ug) categorized by the time to B-cell recovery (recovery < 3 months, >3 months to < 6months, > 6 months) 8 years Relationship between B-cell recovery and transgene levels
Cmax; cellular kinetic parameter of tisagenlecleucel 8 years The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/μg)
Tmax; cellular kinetic parameter of tisagenlecleucel 8 years The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days)
AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel 8 years The AUC from time zero to Tmax in peripheral blood (% or copies/μg x days)
T1/2; cellular kinetic parameter of tisagenlecleucel 8 years The half-life associated with the elimination phase slope of a semi logarithmic concentration-time curve (days) in peripheral blood
Clast; cellular kinetic parameter of tisagenlecleucel 8 years The last observed quantifiable concentration in peripheral blood (% or copies/μg)
AUC 0 - 29d; cellular kinetic parameter of tisagenlecleucel 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 )
Tmax: cellular kinetic parameter of tisagenlecleucel 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)
European Quality of Life 5 dimensions (EQ-5D-3L & EQ-5D-Y)) 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).Tlast; cellular kinetic parameter of tisagenlecleucel 8 years The time of last observed quantifiable concentration in peripheral blood (days)
Cmax: cellular kinetic parameter of tisagenlecleucel 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)
tisagenlecleucel transgene concentration 8 years Transgene concentration as detected by qPCR in target tissue
T1/2: cellular kinetic parameter of tisagenlecleucel 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
Trial Locations
- Locations (33)
Dana Farber Cancer Institute Dept.of DFCI
🇺🇸Boston, Massachusetts, United States
Methodist Childrens Hospital .
🇺🇸San Antonio, Texas, United States
City of Hope National Medical
🇺🇸Duarte, California, United States
Childrens Hospital Los Angeles SC CTL019
🇺🇸Los Angeles, California, United States
Mattel Childrens Hospital UCLA
🇺🇸Los Angeles, California, United States
Childrens Hospital of Orange County CHOC Childrens
🇺🇸Orange, California, United States
Stanford University Medical Center .
🇺🇸Stanford, California, United States
Rady Children s Hospital CTBM100C2401
🇺🇸San Diego, California, United States
Childrens National Hospital
🇺🇸Washington, District of Columbia, United States
Johns Hopkins All Childrens
🇺🇸Saint Petersburg, Florida, United States
Childrens Healthcare of Atlanta Emory University IRB
🇺🇸Atlanta, Georgia, United States
James Whitcomb Riley Hospital For Children
🇺🇸Indianapolis, Indiana, United States
Johns Hopkins Oncology Center Cancer Research Building
🇺🇸Baltimore, Maryland, United States
Children s Mercy Hospital
🇺🇸Kansas City, Missouri, United States
Hackensack Univ Medical Center
🇺🇸Hackensack, New Jersey, United States
Roswell Park Cancer Institute Main Centre
🇺🇸Buffalo, New York, United States
Memorial Sloan Kettering Cancer Ctr .
🇺🇸New York, New York, United States
Columbia University Medical Center Oncology
🇺🇸New York, New York, United States
Duke University Medical Center .
🇺🇸Durham, North Carolina, United States
Cinn Children Hosp Medical Center
🇺🇸Cincinnati, Ohio, United States
The Childrens Hosp of Philadelphia Div Gastroint Hepat and Nutr
🇺🇸Philadelphia, Pennsylvania, United States
Texas Childrens Cancer and Hematology Center
🇺🇸Houston, Texas, United States
Univ of Texas Southwest Med Center
🇺🇸Dallas, Texas, United States
University of Wisconsin Hospital and Clinics Pharmacy/Drug Shipping Address
🇺🇸Madison, Wisconsin, United States
Prinses Maxima Centrum voor Kinderoncologie
🇳🇱Utrecht, CS, Netherlands
Novartis Investigative Site
🇬🇧London, United Kingdom
UCSF Medical Center .
🇺🇸San Francisco, California, United States
University of Utah Clinical Trials Office .
🇺🇸Salt Lake City, Utah, United States
Children s Hospital of Alabama
🇺🇸Birmingham, Alabama, United States
Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
Oregon Health and Science University .
🇺🇸Portland, Oregon, United States
Childrens Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Childrens Hospital Colorado .
🇺🇸Aurora, Colorado, United States