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

B-Cell Acute Lymphoblastic Leukemia Clinical Trial

— CASSIOPEIA  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03876769
• Other study ID #: CCTL019G2201J
• Secondary ID: 2017-002116-14
• Status: Recruiting
• Phase: Phase 2
• Start date: June 24, 2019
• Est. completion date: October 19, 2027

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: 1-888-669-6682
• Email: novartis.email[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: October 19, 2027
• Est. primary completion date: October 19, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 25 Years

Eligibility

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.

Related Conditions & MeSH terms

• B-Cell Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Gent
Canada	Novartis Investigative Site	Calgary	Alberta
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Denmark	Novartis Investigative Site	Copenhagen
Finland	Novartis Investigative Site	Helsinki
France	Novartis Investigative Site	Paris
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Muenchen
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Roma	RM
Netherlands	Prinses Maxima Centrum voor Kinderoncologie	Utrecht	CS
Norway	Novartis Investigative Site	Oslo
Spain	Novartis Investigative Site	Esplugues De Llobregat	Barcelona
Sweden	Novartis Investigative Site	Goteborg
Sweden	Novartis Investigative Site	Stockholm
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United States	University of Michigan	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta Emory University IRB	Atlanta	Georgia
United States	Childrens Hospital Colorado .	Aurora	Colorado
United States	Johns Hopkins Oncology Center Cancer Research Building	Baltimore	Maryland
United States	Children s Hospital of Alabama	Birmingham	Alabama
United States	Dana Farber Cancer Institute Dept.of DFCI	Boston	Massachusetts
United States	Roswell Park Cancer Institute Main Centre	Buffalo	New York
United States	Medical Uni of South Carolina Medical Univ of SC	Charleston	South Carolina
United States	Ann and Robert H Lurie Childrens Hospital of Chicago .	Chicago	Illinois
United States	University of Chicago Hospital .	Chicago	Illinois
United States	Cinn Children Hosp Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation Main Centre	Cleveland	Ohio
United States	Univ Hospital - Cleveland/Rainbow Babies and Children's Hosp Pediatric Nephrology	Cleveland	Ohio
United States	Nationwide Childrens Hospital suite T6B	Columbus	Ohio
United States	Univ of Texas Southwest Med Center	Dallas	Texas
United States	City of Hope National Medical	Duarte	California
United States	Duke University Medical Center .	Durham	North Carolina
United States	Hackensack Univ Medical Center	Hackensack	New Jersey
United States	Penn State Childrens Hospital	Hershey	Pennsylvania
United States	Texas Children's Cancer and Hematology Center	Houston	Texas
United States	James Whitcomb Riley Hospital for Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center Childrens Hospital .	Jackson	Mississippi
United States	Children s Mercy Hospital	Kansas City	Missouri
United States	Childrens Hospital Los Angeles SC CTL019	Los Angeles	California
United States	Mattel Childrens Hospital UCLA	Los Angeles	California
United States	Norton Children s Hospital	Louisville	Kentucky
United States	University of Wisconsin Hospital and Clinics Pharmacy/Drug Shipping Address	Madison	Wisconsin
United States	Childrens Hospital of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota CAEB071B2201	Minneapolis	Minnesota
United States	Monroe Carell Jr Childrens Hospital at Vanderbilt	Nashville	Tennessee
United States	Yale School of Medicine	New Haven	Connecticut
United States	Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Columbia University Medical Center Oncology	New York	New York
United States	Memorial Sloan Kettering Cancer Ctr .	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Childrens Hospital of Orange County CHOC Childrens	Orange	California
United States	The Childrens Hosp of Philadelphia Div Gastroint Hepat and Nutr	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Oregon Health and Science University .	Portland	Oregon
United States	Children's Hospital of Richmond at VCU Pediatric Hematology Oncology	Richmond	Virginia
United States	St. Louis University/Cardinal Glennon Children's Hospital	Saint Louis	Missouri
United States	Washington Univ School of Medicine CTBM100C2412	Saint Louis	Missouri
United States	Johns Hopkins All Childrens	Saint Petersburg	Florida
United States	University of Utah Clinical Trials Office .	Salt Lake City	Utah
United States	Methodist Children's Hospital .	San Antonio	Texas
United States	Rady Children s Hospital CTBM100C2401	San Diego	California
United States	UCSF Medical Center .	San Francisco	California
United States	Stanford University Medical Center .	Stanford	California
United States	Childrens National Hospital	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals	Children's Oncology Group

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  Finland,  France,  Germany,  Italy,  Netherlands,  Norway,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Percentage of participants with pre-existing antibodies	Prevalence of immunogenicity	8 years
Secondary	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
Secondary	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
Secondary	tisagenlecleucel transgene concentration	Transgene concentration as detected by qPCR in target tissue	8 years
Secondary	Expression of tisagenlecleucel	Summary of tisagenlecleucel CAR-positive viable T cells measured by flow cytometry in target tissue	8 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel	The AUC from time zero to Tmax in peripheral blood (% or copies/µg x days)	8 years
Secondary	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
Secondary	Clast; cellular kinetic parameter of tisagenlecleucel	The last observed quantifiable concentration in peripheral blood (% or copies/µg)	8 years
Secondary	Tlast; cellular kinetic parameter of tisagenlecleucel	The time of last observed quantifiable concentration in peripheral blood (days)	8 years
Secondary	Impact of tisagenlecleucel dose on day 29 response	Clinical response summarized by quartile of administered doses	8 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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