Clinical trial NCT03876769: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: B-Cell Acute Lymphoblastic Leukemia
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)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Children's Oncology Group
First posted: 2019-03-15
Enrollment: 121
Sex: ALL
Minimum age (years): 1
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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, 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.

Primary outcomes:
measure: Disease Free Survival (DFS) rate without censoring for new anticancer therapy, including Stem Cell Transplantation (SCT) while in remission
timeFrame: 5 years after tisagenlecleucel infusion
measure: Overall Survival (OS) rate
timeFrame: 4 years after tisagenlecleucel
Secondary outcomes:
measure: Percentage of participants who are disease free without allogeneic stem cell transplant (SCT)
timeFrame: 12 months after last infusion
measure: DFS rate with censoring for new anticancer therapy, including SCT, while in remission
timeFrame: 5 years
measure: Percentage of participants achieving MRD negative CR or CRi at Month 3
timeFrame: 3 months after the tisagenlecleucel infusion.
measure: Percentage of participants with in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion
timeFrame: 8 years
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
timeFrame: 8 years
measure: Pediatric Quality of Life (PedsQL)
timeFrame: 5 years
measure: European Quality of Life 5 dimensions (EQ-5D-3L & EQ-5D-Y))
timeFrame: 5 years
measure: Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Detection test
timeFrame: 5 years
measure: Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: Identification test
timeFrame: 5 years
measure: Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Groton Maze Learning test
timeFrame: 5 years
measure: Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: One Back test
timeFrame: 5 years
measure: Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: One card learning test
timeFrame: 5 years
measure: Percentage of participants with pre-existing antibodies
timeFrame: 8 years
measure: Percentage of participants with anti-m CAR19 antibodies post infusion with tisagenlecleucel and % of patients without measureable anti-mCAR19 antibodies
timeFrame: 8 years
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
timeFrame: 8 years
measure: tisagenlecleucel transgene concentration
timeFrame: 8 years
measure: Expression of tisagenlecleucel
timeFrame: 8 years
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)
timeFrame: 8 years
measure: Cmax; cellular kinetic parameter of tisagenlecleucel
timeFrame: 8 years
measure: Tmax; cellular kinetic parameter of tisagenlecleucel
timeFrame: 8 years
measure: AUC0-29d and 84d; cellular kinetic parameter of tisagenlecleucel
timeFrame: 8 years
measure: AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel
timeFrame: 8 years
measure: T1/2; cellular kinetic parameter of tisagenlecleucel
timeFrame: 8 years
measure: Clast; cellular kinetic parameter of tisagenlecleucel
timeFrame: 8 years
measure: Tlast; cellular kinetic parameter of tisagenlecleucel
timeFrame: 8 years
measure: Impact of tisagenlecleucel dose on day 29 response
timeFrame: 8 years
measure: AUC 0 - 29d; cellular kinetic parameter of tisagenlecleucel
timeFrame: Day 29
measure: Cmax: cellular kinetic parameter of tisagenlecleucel
timeFrame: Day 29
measure: Tmax: cellular kinetic parameter of tisagenlecleucel
timeFrame: Day 29
measure: T1/2: cellular kinetic parameter of tisagenlecleucel
timeFrame: Day 29
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children s Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Duarte
country: United States
facility: City of Hope National Medical
state: California
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles SC CTL019
state: California
city: Los Angeles
country: United States
facility: Mattel Childrens Hospital UCLA
state: California
city: Orange
country: United States
facility: Childrens Hospital of Orange County CHOC Childrens
state: California
city: San Diego
country: United States
facility: Rady Children s Hospital CTBM100C2401
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center .
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center .
state: California
city: Aurora
country: United States
facility: Childrens Hospital Colorado .
state: Colorado
city: Washington
country: United States
facility: Childrens National Hospital
state: District of Columbia
city: Saint Petersburg
country: United States
facility: Johns Hopkins All Childrens
state: Florida
city: Atlanta
country: United States
facility: Childrens Healthcare of Atlanta Emory University IRB
state: Georgia
city: Indianapolis
country: United States
facility: James Whitcomb Riley Hospital For Children
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins Oncology Center Cancer Research Building
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute Dept.of DFCI
state: Massachusetts
city: Kansas City
country: United States
facility: Children s Mercy Hospital
state: Missouri
city: Hackensack
country: United States
facility: Hackensack Univ Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute Main Centre
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Ctr .
state: New York
city: New York
country: United States
facility: Columbia University Medical Center Oncology
state: New York
city: Durham
country: United States
facility: Duke University Medical Center .
state: North Carolina
city: Cincinnati
country: United States
facility: Cinn Children Hosp Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University .
state: Oregon
city: Philadelphia
country: United States
facility: The Childrens Hosp of Philadelphia Div Gastroint Hepat and Nutr
state: Pennsylvania
city: Dallas
country: United States
facility: Univ of Texas Southwest Med Center
state: Texas
city: Houston
country: United States
facility: Texas Childrens Cancer and Hematology Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Childrens Hospital .
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Clinical Trials Office .
state: Utah
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics Pharmacy/Drug Shipping Address
state: Wisconsin
city: Milwaukee
country: United States
facility: Childrens Hospital of Wisconsin
state: Wisconsin
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Utrecht
country: Netherlands
facility: Prinses Maxima Centrum voor Kinderoncologie
state: CS
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Esplugues De Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Goteborg
country: Sweden
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Seftel MD. Hyper-CVAD: a regimen for all seasons. Lancet Haematol. 2020 Jul;7(7):e501-e502. doi: 10.1016/S2352-3026(20)30179-4. No abstract available.