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

Phase 2Active Not RecruitingNCT03876769

Novartis Pharmaceuticals122 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

122

Conditions

B-Cell Acute Lymphoblastic Leukemia

Interventions

Eligibility

Sex: ALLMin age: 1 YearMax age: 25 Years

Medical Language ↔ Plain English

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, Berlin-Frankfurt-Münster (BFM) consolidation or Phase 1b, 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 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. 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.

Locations (45)

Children s Hospital of Alabama

Birmingham, Alabama, United States

Phoenix Childrens Hospital

Phoenix, Arizona, United States

City of Hope National Medical

Duarte, California, United States

Childrens Hospital Los Angeles

Los Angeles, California, United States

Mattel Childrens Hospital UCLA

Los Angeles, California, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 4 years after tisagenlecleucel

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 3 months after the tisagenlecleucel infusion.

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).

Time frame: 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).

Time frame: 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)

Time frame: 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)

Time frame: 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.

Time frame: 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).

Time frame: 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).

Time frame: 5 years

Percentage of participants with pre-existing antibodies

Prevalence of immunogenicity

Time frame: 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

Time frame: 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

Time frame: 8 years

tisagenlecleucel transgene concentration

Transgene concentration as detected by qPCR in target tissue

Time frame: 8 years

Expression of tisagenlecleucel

Summary of tisagenlecleucel CAR-positive viable T cells measured by flow cytometry in target tissue

Time frame: 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

Time frame: 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)

Time frame: 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)

Time frame: 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 )

Time frame: 8 years

AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel

The AUC from time zero to Tmax in peripheral blood (% or copies/μg x days)

Time frame: 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

Time frame: 8 years

Clast; cellular kinetic parameter of tisagenlecleucel

The last observed quantifiable concentration in peripheral blood (% or copies/μg)

Time frame: 8 years

Tlast; cellular kinetic parameter of tisagenlecleucel

The time of last observed quantifiable concentration in peripheral blood (days)

Time frame: 8 years

Impact of tisagenlecleucel dose on day 29 response

Clinical response summarized by quartile of administered doses

Time frame: 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 )

Time frame: 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)

Time frame: 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)

Time frame: 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

Time frame: Day 29