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JOURNAL ONKOLOGIE – STUDIE
CASSIOPEIA

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

Rekrutierend

NCT-Nummer:
NCT03876769

Studienbeginn:
Juni 2019

Letztes Update:
25.03.2024

Wirkstoff:
CTL019

Indikation (Clinical Trials):
Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphoid

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
Phase 2

Sponsor:
Novartis Pharmaceuticals

Collaborator:
Children's Oncology Group

Studienleiter

Novartis Pharmaceuticals
Study Director
Novartis Pharmaceuticals

Kontakt

Studienlocations
(3 von 68)

Novartis Investigative Site
60590 Frankfurt
(Hessen)
GermanyZurückgezogen» Google-Maps
Novartis Investigative Site
20246 Hamburg
(Hamburg)
GermanyZurückgezogen» Google-Maps
Novartis Investigative Site
81377 Muenchen
(Bayern)
GermanyZurückgezogen» Google-Maps
Yale School of Medicine
06519 New Haven
United StatesRekrutierend» Google-Maps
Ann and Robert H Lurie Childrens Hospital of Chicago .
60611 Chicago
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Eric Brown
Phone: 312-227-4811
E-Mail: errbrown@luriechildrens.org» Ansprechpartner anzeigen
University of Chicago Hospital .
60637 Chicago
United StatesRekrutierend» Google-Maps
Norton Children s Hospital
40202 Louisville
United StatesZurückgezogen» Google-Maps
Johns Hopkins Oncology Center Cancer Research Building
21231 Baltimore
United StatesAktiv, nicht rekrutierend» Google-Maps
Dana Farber Cancer Institute Dept.of DFCI
02215 Boston
United StatesAktiv, nicht rekrutierend» Google-Maps
University of Mississippi Medical Center Childrens Hospital .
39216 Jackson
United StatesZurückgezogen» Google-Maps
Children s Mercy Hospital
64108 Kansas City
United StatesAktiv, nicht rekrutierend» Google-Maps
St. Louis University/Cardinal Glennon Children's Hospital
63104 Saint Louis
United StatesZurückgezogen» Google-Maps
Washington Univ School of Medicine CTBM100C2412
63110 Saint Louis
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Bethany Kellogg
Phone: 314-454-2253
E-Mail: bethany.kellogg@wustl.edu» Ansprechpartner anzeigen
University of Nebraska Medical Center
68198 Omaha
United StatesZurückgezogen» Google-Maps
Hackensack Univ Medical Center
07601 Hackensack
United StatesAktiv, nicht rekrutierend» Google-Maps
Cohen Children's Medical Center of New York
11040 New Hyde Park
United StatesZurückgezogen» Google-Maps
Memorial Sloan Kettering Cancer Ctr .
10065 New York
United StatesAktiv, nicht rekrutierend» Google-Maps
Columbia University Medical Center Oncology
110032 New York
United StatesAktiv, nicht rekrutierend» Google-Maps
Univ Hospital - Cleveland/Rainbow Babies and Children's Hosp Pediatric Nephrology
44106 Cleveland
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Jahnahn Taghiani
Phone: 218-844-3681
E-Mail: Jahnahn.Taghiani@UHhospitals.org» Ansprechpartner anzeigen
Nationwide Childrens Hospital suite T6B
43205 Columbus
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Trittnee Robinson
Phone: 614-722-2556
E-Mail: Trittnee.Robinson@nationwidechildrens.org» Ansprechpartner anzeigen
Penn State Childrens Hospital
17033 Hershey
United StatesZurückgezogen» Google-Maps
The Childrens Hosp of Philadelphia Div Gastroint., Hepat. & Nutr.
19104 Philadelphia
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Aakruti Sharma
Phone: 215-590-2985
E-Mail: sharmaa16@chop.edu» Ansprechpartner anzeigen
Children's Hospital of Richmond at VCU Pediatric Hematology Oncology
23219 Richmond
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Grace Garren
Phone: 804-828-9605
E-Mail: garreng@vcu.edu» Ansprechpartner anzeigen
University of Wisconsin Hospital and Clinics Pharmacy/Drug Shipping Address
53792 Madison
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Jenny Weiland
E-Mail: PedsHemOncResearch@lists.wisc.edu» Ansprechpartner anzeigen
Novartis Investigative Site
T3B 6A8 Calgary
CanadaRekrutierend» Google-Maps
Novartis Investigative Site
M5G 1X8 Toronto
CanadaAktiv, nicht rekrutierend» Google-Maps
Novartis Investigative Site
H3T 1C5 Montreal
CanadaRekrutierend» Google-Maps
Novartis Investigative Site
2100 Copenhagen
DenmarkAktiv, nicht rekrutierend» Google-Maps
Novartis Investigative Site
00029 Helsinki
FinlandZurückgezogen» Google-Maps
Novartis Investigative Site
75019 Paris
FranceAktiv, nicht rekrutierend» Google-Maps
Prinses Maxima Centrum voor Kinderoncologie
3584 Utrecht
NetherlandsRekrutierend» Google-Maps
Novartis Investigative Site
08950 Esplugues De Llobregat
SpainRekrutierend» Google-Maps
Novartis Investigative Site
SE 416 85 Goteborg
SwedenRekrutierend» Google-Maps
Novartis Investigative Site
141 86 Stockholm
SwedenRekrutierend» Google-Maps
Novartis Investigative Site
WC1E 6HX London
United KingdomRekrutierend» Google-Maps
Novartis Investigative Site
WC1N 3JH London
United KingdomRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Disease Free Survival (DFS) rate without censoring for new anticancer therapy, including Stem Cell Transplantation (SCT) while in remission (Time Frame - 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.

2. Overall Survival (OS) rate (Time Frame - 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:

1. Percentage of participants who are disease free without allogeneic stem cell transplant (SCT) (Time Frame - 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.

2. DFS rate with censoring for new anticancer therapy, including SCT, while in remission (Time Frame - 5 years):
Assessing the effect of tisagenlecleucel on DFS if new anticancer therapy is not available.

3. Percentage of participants achieving MRD negative CR or CRi at Month 3 (Time Frame - 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.

4. Percentage of participants with in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion (Time Frame - 8 years):
Absolute lymphocyte CD19 count of <50/uL

5. Percentage of participants who have tisagenlecleucel product successfully manufactured over the total number of subjects enrolled for the age ≥1 year and < 3 years (Time Frame - 8 years):
Success in manufacturing of tisagenlecleucel dose for patients who are ≥1 year and <3 years as respective time points.

6. Pediatric Quality of Life (PedsQL) (Time Frame - 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).

7. European Quality of Life 5 dimensions (EQ-5D-3L & EQ-5D-Y)) (Time Frame - 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).

8. Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Detection test (Time Frame - 5 years):
Speed of performance (mean of the log10 transformed reaction times for correct responses)

9. Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: Identification test (Time Frame - 5 years):
This test measures the speed of performance (mean of the log10 transformed reaction times for correct responses)

10. Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: Groton Maze Learning test (Time Frame - 5 years):
This test looks at the total number of errors made in attempting to learn the hidden pathways during a single session.

11. Impact of tisagenlecleucel on cognitive functioning using Computerized neurocognitive assessment: One Back test (Time Frame - 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).

12. Impact of tisagenlecleucel on cognitive functioning usingComputerized neurocognitive assessment: One card learning test (Time Frame - 5 years):
This test measures the accuracy of performance (arcsine transformation of the square root of the proportion of correct responses).

13. Percentage of participants with pre-existing antibodies (Time Frame - 8 years):
Prevalence of immunogenicity

14. Percentage of participants with anti-m CAR19 antibodies post infusion with tisagenlecleucel and % of patients without measureable anti-mCAR19 antibodies (Time Frame - 8 years):
Incidence of immunogenicity

15. 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 (Time Frame - 8 years):
Impact of immunogenicity on clinical response

16. tisagenlecleucel transgene concentration (Time Frame - 8 years):
Transgene concentration as detected by qPCR in target tissue

17. Expression of tisagenlecleucel (Time Frame - 8 years):
Summary of tisagenlecleucel CAR-positive viable T cells measured by flow cytometry in target tissue

18. Persistence of CAR (reported as copies/ug) categorized by the time to B-cell recovery (recovery < 3 months, >3 months to < 6months, > 6 months) (Time Frame - 8 years):
Relationship between B-cell recovery and transgene levels

19. Cmax; cellular kinetic parameter of tisagenlecleucel (Time Frame - 8 years):
The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/μg)

20. Tmax; cellular kinetic parameter of tisagenlecleucel (Time Frame - 8 years):
The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days)

21. AUC0-29d and 84d; cellular kinetic parameter of tisagenlecleucel (Time Frame - 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 )

22. AUC0-Tmax; cellular kinetic parameter of tisagenlecleucel (Time Frame - 8 years):
The AUC from time zero to Tmax in peripheral blood (% or copies/μg x days)

23. T1/2; cellular kinetic parameter of tisagenlecleucel (Time Frame - 8 years):
The half-life associated with the elimination phase slope of a semi logarithmic concentration-time curve (days) in peripheral blood

24. Clast; cellular kinetic parameter of tisagenlecleucel (Time Frame - 8 years):
The last observed quantifiable concentration in peripheral blood (% or copies/μg)

25. Tlast; cellular kinetic parameter of tisagenlecleucel (Time Frame - 8 years):
The time of last observed quantifiable concentration in peripheral blood (days)

26. Impact of tisagenlecleucel dose on day 29 response (Time Frame - 8 years):
Clinical response summarized by quartile of administered doses

27. AUC 0 - 29d; cellular kinetic parameter of tisagenlecleucel (Time Frame - 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 )

28. Cmax: cellular kinetic parameter of tisagenlecleucel (Time Frame - 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)

29. Tmax: cellular kinetic parameter of tisagenlecleucel (Time Frame - 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)

30. T1/2: cellular kinetic parameter of tisagenlecleucel (Time Frame - 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

Geprüfte Regime

  • 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

Quelle: ClinicalTrials.gov


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