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JOURNAL ONKOLOGIE – STUDIE

A Study to Evaluate the Safety and Efficacy of JCAR017 in Pediatric Subjects With Relapsed/Refractory (r/r) B-cell Acute Lymphoblastic Leukemia (B-ALL) and B-cell Non-Hodgkin Lymphoma (B-NHL)

Rekrutierend

NCT-Nummer:
NCT03743246

Studienbeginn:
Oktober 2018

Letztes Update:
28.04.2021

Wirkstoff:
JCAR017, Lymphodepleting, Fludarabine, Cyclophosphamide

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

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Celgene

Collaborator:
-

Studienleiter

Ettore Biagi, MD, PhD
Study Director
Celgene

Kontakt

Associate Director Clinical Trial Disclosure
Kontakt:
Phone: 1-888-260-1599
E-Mail: clinicaltrialdisclosure@celgene.com
» Kontaktdaten anzeigen

Studienlocations
(3 von 14)

Charite Campus Virchow
13353 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps
Klinikum der Johann Wolfgang Goethe-Universitaet Frankfurt
60590 Frankfurt am Main
(Hessen)
GermanyRekrutierend» Google-Maps
Memorial Sloan Kettering Cancer Center
10021 New York
United StatesNoch nicht rekrutierend» Google-Maps
The Children's Hospital of Philadelphia
19104 Philadelphia
United StatesAktiv, nicht rekrutierend» Google-Maps
Seattle Children's Hospital
98105 Seattle
United StatesRekrutierend» Google-Maps
Institute for Pediatric Hematology - Oncology, Leon Berard Cancer Center
69008 Lyon
FranceNoch nicht rekrutierend» Google-Maps
Hopital d'Enfants de la Timone
13005 Marseille Cedex 01
FranceNoch nicht rekrutierend» Google-Maps
Princess Maxima Center for Pediatric Oncology
3584 CS Utrecht
NetherlandsRekrutierend» Google-Maps
Hospital San Joan de Deu Barcelona
08950 Esplugues de Llobregat
SpainRekrutierend» Google-Maps
Hospital Infantil Universitario Nino Jesus
28009 Madrid
SpainRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

This is a Phase 1/2, open-label, single arm, multicohort study incorporating Simon's Optimal

two-stage design to evaluate the safety and efficacy of JCAR017 in pediatric subjects aged ≤

25 years with CD19+ r/r B-ALL and B-NHL.

In the Phase 1, up to 5 dose levels will be of JCAR017 will be evaluated. Enrollment will

commence in pediatric subjects with r/r B-ALL at Dose Level 1 (DL1) of 0.05x10^6 CAR+ T

cells/kg (maximum DL1 of 5x10^6 JCAR017 CAR+ T cells [non-weight adjusted]). If this dose is

confirmed to be safe and tolerable, additional subjects will be enrolled at higher dose(s) up

to 0.75 x10^6 CAR+ T cells/kg (maximum of 75x10^6 JCAR017 CAR+ T cells [non-weight adjusted])

with the aim to identify the RP2D. Dose escalation/de-escalation will follow a modified

toxicity probability interval (mTPI-2) algorithm. A Safety Review Committee (SRC) will

recommend the Phase 2 dose (defined as RP2D) based on an integrated assessment of the safety,

PK and preliminary efficacy information from at least 10 pediatric subjects treated at the

RP2D.

In Phase 2, a minimum of 71 additional subjects (< 18 years of age) will be enrolled into one

of the 3 cohorts listed below. The sample size for Cohorts 1 and 2 is calculated according to

Simon's Optimal two-stage design. The 10 or more pediatric subjects treated at the RP2D in

Phase 1 will form part of the sample size (ie, Cohort 1 and Cohort 2). Therefore, the

protocol intends to treat 81 primary endpoint evaluable pediatric subjects in Phase 2, if

warranted by the evaluation of results at the completion of the first stage of the study in

each cohort.

- Cohort 1 (r/r B-ALL): 48 evaluable pediatric subjects (13 subjects in Stage 1 and 35 in

Stage 2)

- Cohort 2 (MRD+ B-ALL): 23 evaluable pediatric subjects (9 subjects in Stage 1 and 14

subjects in Stage 2)

- Cohort 3 (r/r B-NHL [DLBCL, BL, or PMBCL]): 10 evaluable pediatric subjects. Due to the

very low incidence rate and therefore expected low subject accrual, there is no formal

sample size for this arm.

Up to 20 additional B-ALL subjects between 18 and 25 years of age may be enrolled in Phase 2.

Following treatment with JCAR017 subjects will then enter the post-treatment period for

disease progression/relapse, safety, CAR T cell persistence, and survival up to 24 months

after administration of JCAR017.

Efficacy will be assessed both locally and by an Independent Review Committee. Response

assessments will be based on bone marrow and blood morphologic criteria, physical examination

findings, along with laboratory assessments of cerebral spinal fluid (CSF) and bone marrow

MRD (B-ALL only) assessments. B-NHL subjects will also have radiographic disease assessment

by CT/MRI scans and tumor biopsies, if accessible.

Post-study follow-up for survival, relapse, long-term toxicity, and lentiviral vector safety

will continue under a separate long-term follow-up protocol for up to 15 years after the

JCAR017 infusion as per health authority regulatory guidelines.

An Independent Data Monitoring Committee will monitor the study conduct.

Ein-/Ausschlusskriterien

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Phase 1: Subject < 18 years of age and weighs ≥ 6 kg at the time of signing the

informed consent form (ICF)/informed assent form (IAF).

Phase 2: Subject ≤ 25 years of age and weighs ≥ 6 kg at the time of signing the

ICF/IAF.

2. Subject (when applicable, parental/legal representative) must understand and

voluntarily provide permission to the ICF/IAF prior to conducting any study-related

assessments/procedures.

3. Subject is willing and able to adhere to the study visit schedule and other protocol

requirements.

4. Investigator considers the subject is appropriate for adoptive T cell therapy.

5. Evidence of CD19 expression via flow cytometry (peripheral blood or bone marrow) or

immunohistochemistry (bone marrow biopsy)

6. Subject has a Karnofsky score of ≥ 50 (subjects ≥ 16 years of age) or a Lansky score ≥

50 (subjects < 16 years of age).

7. Diagnosis of B-cell ALL or B-cell NHL as defined below:

Phase 1: Subjects with r/r B-ALL, defined as morphological evidence of disease in BM

(5% or greater lymphoblast by morphology) and either of the following:

- First or greater marrow relapse, or

- Any marrow relapse after allogeneic HSCT, or

- Primary refractory defined as not achieving a CR or a CRi after 2 or more

separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1

cycle of standard chemotherapy for relapsed leukemia), or

- Ineligible for allogeneic HSCT Note: Subjects will be included regardless of MRD

status.

Phase 2: Subjects with one of the following:

- Cohort 1: r/r B-ALL, defined as morphological evidence of disease in BM (5% or

greater lymphoblast by morphology) and either:

- First or greater marrow relapse, or

- Any marrow relapse after allogeneic HSCT, or

- Primary refractory defined as not achieving a CR or a CRi after 2 or more

separate induction regimens (or chemo-refractory as not achieving CR/CRi

after 1 cycle of standard chemotherapy for relapsed leukemia), or

- Ineligible for allogeneic HSCT.

- Cohort 2: MRD+ B-ALL, defined as:

- < 5% lymphoblasts by morphology with,

- MRD detected by a validated assay at a frequency of 1 x10-4 or greater in BM

cells. Subjects eligible for enrollment in Cohort 2 are those with MRD

positive morphologic CR2 after re-induction when these subjects had

previously experienced an early relapse (< 36 months) after first-line

chemotherapy. Subjects who are in MRD+ morphologic CR3 and later, regardless

of time to relapse in earlier lines, are also eligible. Subjects who are in

morphologic relapse at screening (r/r B-ALL) and become MRD+ after bridging

chemotherapy are also eligible for treatment in Cohort 2.

- Cohort 3: r/r B-NHL (DLBCL, BL or PMBCL), defined as measurable disease after 1

or more lines of chemotherapy and/or having failed HSCT or being ineligible for

HSCT.

Note: B-NHL subjects with secondary CNS lymphoma involvement are eligible however

subject selection must consider clinical risk factors for severe neurological AEs and

alternative treatment options. Subjects should only be enrolled if the Investigator

considers the potential benefit outweighs the risk for the subject.

8. Subjects with Philadelphia chromosome positive ALL are eligible if they are intolerant

to or have failed one or more lines of tyrosine-kinase inhibitor (TKI) therapy or if

TKI therapy is contraindicated.

9. Adequate organ function, defined as:

- Adequate BM function to receive LD chemotherapy as assessed by the Investigator.

- Subject with adequate renal function, which is defined as:

Serum creatinine based on age/gender as described below. Subjects that do not meet the

criteria but who have a creatinine clearance or radioisotope glomerular filtration

rate (GFR) > 70 mL/min/1.73 m2 are eligible.• Alanine aminotransferase (ALT) ≤ 5 x

upper limit of normal (ULN) and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for

subjects with Gilbert's syndrome or leukemic/lymphomatous infiltration of the liver).

- Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to Common

Toxicity Criteria for Adverse Events (CTCAE) and oxygen saturation (SaO2) ≥ 92%

on room air.

- Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥

40% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA)

within 4 weeks prior to leukapheresis.

10. Adequate vascular access for leukapheresis procedure.

11. Participants must agree to use effective contraception

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

1. Subject has any significant medical condition, laboratory abnormality, or psychiatric

illness that would prevent the subject from participating in the study.

2. Subject has any condition including the presence of laboratory abnormalities, which

places the subject at unacceptable risk if he/she were to participate in the study.

3. Subject has any condition that confounds the ability to interpret data from the study.

4. Subject with a history of another primary malignancy that has not been in remission

for at least 2 years prior to enrollment.

5. Subjects who have received previous CD19-targeted therapy must have CD19-positive

disease confirmed since completing the prior CD19-targeted therapy.

6. Prior CAR T cell or other genetically-modified T cell therapy.

7. Subject with a previous history of or active hepatitis B, hepatitis C, or human

immunodeficiency virus (HIV) infection.

8. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection

(including tuberculosis) despite appropriate antibiotics or other treatment at the

time of leukapheresis or JCAR017 infusion.

9. Subject has presence of acute or chronic graft-versus-host disease (GVHD).

10. Subject with active autoimmune disease requiring immunosuppressive therapy.

11. Subject has cardiac disorders (CTCAE version 4.03 Grade 3 or 4) within the past 6

months.

12. Subject with a concomitant genetic syndrome, with the exception of Down's syndrome.

13. Subject with active CNS disease and significant neurological deterioration. Subjects

with CNS-2 or CNS-3 involvement are eligible provided they are asymptomatic and do not

have significant neurological deterioration and, in the opinion of the study

investigator, the CNS disease burden can be controlled until JCAR017 infusion.

14. Subject with a history or presence of clinically relevant CNS pathology such as

epilepsy, seizure, paresis, aphasia, stroke, cerebral edema, severe brain injuries,

dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or

psychosis.

15. Subject is pregnant or nursing.

16. Subject has used the following:

- Therapeutic doses of corticosteroids (defined as > 0.4 mg/kg maximum 20 mg/day

prednisone or equivalent) within 7 days prior to leukapheresis or 72 hours prior

to JCAR017 infusion. Physiologic replacement, topical, and inhaled steroids are

permitted.

- Low-dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide ≤ 300 mg/m2)

given after leukapheresis to maintain disease control must be stopped ≥ 7 days

prior to LD chemotherapy.

- Cytotoxic chemotherapeutic agents that are not considered lymphotoxic within 1

week prior to leukapheresis. Oral anticancer agents are allowed if at least 3

half-lives have elapsed prior to leukapheresis.

- Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide,

bendamustine) within 2 weeks prior to leukapheresis.

- Experimental agents within 4 weeks prior to leukapheresis unless no response or

PD is documented on the experimental therapy and at least 3 half-lives have

elapsed prior to leukapheresis.

- Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017

infusion (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics,

mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as

antitumor necrosis factor [TNF], anti-IL-6, or anti-IL-6R).

- Donor lymphocyte infusions (DLI) within 6 weeks prior to JCAR017 infusion.

- Radiation within 6 weeks prior to leukapheresis. Subjects must have PD in

irradiated lesions or have additional non-irradiated lesions to be eligible.

Radiation to a single lesion, if additional non-irradiated, measurable lesions

are present, is allowed up to 2 weeks prior to leukapheresis.

- Allogeneic HSCT within 90 days prior to leukapheresis.

17. Tumor invasion of venous or arterial vessels (B-NHL subjects only).

18. Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE) within 3 months prior to

leukapheresis. Subjects with DVT or PE that occurred longer than 3 months prior to

leukapheresis, who still require ongoing therapeutic levels of anti-coagulation

therapy, are also excluded.

19. Existence of CD19-negative clone(s) of leukemia cells

Studien-Rationale

Primary outcome:

1. Recommended Phase 2 Dose (RP2D) of JCAR017 (Time Frame - 28 days after JCAR017 infusion):
The dose recommended for use in phase 2 studies on the basis of dose limiting toxicities observed in phase 1 studies.

2. Overall response rate (ORR)- Cohort 1 (Time Frame - Up to day 56):
Total number of subjects achieving a Complete response (CR) or CR with incomplete blood count recovery (CRi) on Day 28 and confirmed on Day 56 as determined by IRC assessment.

3. Minimal residual disease (MRD) negative rate - Cohort 2 (Time Frame - Up to day 56):
Total number of subjects achieving a CR or CRi with an MRD negative bone marrow (<0.01% tumor cells) on Day 28 and confirmed on Day 56 as determined by IRC assessment.

4. Overall response rate (ORR)- Cohort 3 (Time Frame - On day 28):
Total number of subjects achieving a CR or PR on Day 28 as determined by IRC assessment.

Secondary outcome:

1. Adverse Events (AEs) (Time Frame - Up to 2 years after JCAR017 infusion):
Type, frequency and severity of adverse events (AEs), serious adverse events (SAE), and laboratory abnormalities (overall and in clinical, histological and molecular subgroups)

2. Overall response rate (ORR) in the non-selected dose levels from Phase 1 (Time Frame - On day 28 and day 56):
Percentage of r/r B-ALL subjects achieving a best overall response (BOR) of CR or CRi on Day 28, confirmed on Day 56 as determined by IRC assessment

3. Duration of response (DOR) (Time Frame - Up to 2 years after JCAR017 infusion):
Time from first response until progressive disease (PD), disease relapse, or death from any cause, whichever occurs first

4. Relapse-free survival (RFS) (Time Frame - Up to 2 years after JCAR017 infusion):
Time from JCAR017 infusion to documentation of PD, disease relapse, or death due to any cause, whichever occurs first

5. Event-free survival (EFS) (Time Frame - Up to 2 years after JCAR017 infusion):
Time from JCAR017 infusion to PD, disease relapse, start of a new anticancer therapy, or death from any cause, whichever occurs first

6. Overall survival (OS) (Time Frame - Up to 2 years after JCAR017 infusion):
Time from JCAR017 infusion to time of death due to any cause

7. MRD negative response rate (Time Frame - Up to 2 years after JCAR017 infusion):
Number of B-ALL subjects achieving CR or CRi and a negative MRD bone marrow.

8. Rate of hematopoietic stem cell transplant (HSCT) after response to JCAR017 infusion (Time Frame - Up to 2 years after JCAR017 infusion):
Percentage of subjects who achieve a response after JCAR017 infusion and then proceed to HSCT

9. Pharmacokinetics - Cmax (Time Frame - Up to 2 years after JCAR017 infusion):
Maximum concentration

10. Pharmacokinetics - Tmax (Time Frame - Up to 2 years after JCAR017 infusion):
Time to peak concentration

11. Pharmacokinetics - AUC (Time Frame - Up to 2 years after JCAR017 infusion):
Area under the curve

12. Best Overall Response (BOR) (Time Frame - Up to 2 years after JCAR017 infusion):
Number of r/r B-NHL subjects achieving BOR of CR/PR

Geprüfte Regime

  • JCAR017:
    JCAR017
  • Lymphodepleting:
    Lymphodepleting
  • Fludarabine:
    Fludarabine
  • Cyclophosphamide:
    Cyclophosphamide

Quelle: ClinicalTrials.gov


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