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

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

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 Overview

• Status: Active, not recruiting
• Conditions: B-Cell Acute Lymphoblastic Leukemia
• Intervention / Treatment: Biological: CTL019

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Novartis Investigative Site
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Novartis Investigative Site
• Denmark
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
• France
  • Paris, France, 75019
    • Novartis Investigative Site
• Italy
  • RM
    • Roma, RM, Italy, 00165
      • Novartis Investigative Site
• Netherlands
  • Utrecht, Netherlands, 3584 CS
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0424
    • Novartis Investigative Site
• Spain
  • Barcelona
    • Esplugues, Barcelona, Spain, 08950
      • Novartis Investigative Site
• Sweden
  • Gothenburg, Sweden, SE 416 85
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, NW1 2BU
    • Novartis Investigative Site
  • London, United Kingdom, WC1N 3JH
    • Novartis Investigative Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Children s Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
    • Los Angeles, California, United States, 90095
      • Mattel Childrens Hospital UCLA
    • Orange, California, United States, 92868-3874
      • Childrens Hospital of Orange County
    • San Diego, California, United States, 92123
      • Rady Children s Hospital
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
    • Stanford, California, United States, 94304
      • Stanford University Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Childrens Hospital Colorado
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Childrens National Hospital
  • Florida
    • St. Petersburg, Florida, United States, 33701
      • Johns Hopkins All Childrens
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Childrens Healthcare of Atlanta
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5225
      • Indiana University
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Oncology Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children s Mercy Hospital
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack Uni Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Ctr
    • New York, New York, United States, 110032
      • Columbia University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cinn Children Hosp Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Childrens Hosp of Philadelphia
  • Texas
    • Dallas, Texas, United States, 75390-9034
      • Univ of Texas Southwest Med Center
    • Houston, Texas, United States, 77030
      • Texas Childrens Cancer and Hematology Center
    • San Antonio, Texas, United States, 78229
      • Methodist Childrens Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Clinical Trials Office
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Childrens Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

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
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
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.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Collaborators: Children's Oncology Group
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• Davis KL, Yao CC, Zimmerman JAO, Rau RE. Immunotherapy in B-Cell Acute Lymphoblastic Leukemia. J Natl Compr Canc Netw. 2025 Dec;23(12):e257067. doi: 10.6004/jnccn.2025.7067.

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2019
• Primary Completion (Estimated): October 19, 2027
• Study Completion (Estimated): October 19, 2027

Study Registration Dates

• First Submitted: November 12, 2018
• First Submitted That Met QC Criteria: March 12, 2019
• First Posted (Actual): March 15, 2019

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: ALL; Minimal Residual Disease (MRD); CTL019; B-Cell Acute Lymphoblastic Leukemia; tisagenlecleucel; Kymriah; HR B-ALL EOC MRD; Positive at the End of Consolidation (EOC)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Immune System Diseases; Infections; Virus Diseases; Neoplasms by Histologic Type; Neoplastic Processes; DNA Virus Infections; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Epstein-Barr Virus Infections; Herpesviridae Infections; Tumor Virus Infections; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Neoplasm, Residual; Burkitt Lymphoma; Antineoplastic Agents, Immunological; Antineoplastic Agents; tisagenlecleucel
• Other Study ID Numbers: CCTL019G2201J; 2017-002116-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No