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JOURNAL ONKOLOGIE – STUDIE

MB-CART19.1 r/r CD19+ B-cell Malignancies (BCM)

Rekrutierend

NCT-Nummer:
NCT03853616

Studienbeginn:
November 2018

Letztes Update:
24.11.2023

Wirkstoff:
MB-CART19.1

Indikation (Clinical Trials):
Lymphoma, Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphoid, Lymphoma, B-Cell, Leukemia, Lymphocytic, Chronic, B-Cell, Recurrence

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Miltenyi Biomedicine GmbH

Collaborator:
-

Studienleiter

Claudia Rössig, Prof. Dr.
Principal Investigator
Univeristy Hospital Muenster

Kontakt

Studienlocations
(3 von 10)

Charité - University clinic, pediatric clinic with focus on oncology and hematology
13353 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Annette Kuenkele, Dr.
Phone: +49 30 450 616 178
E-Mail: annette.kuenkele@charite.de

Arend von Stackelberg, PD, Dr.
Phone: +49 30 450 666 833
E-Mail: arend.stackelberg@charite.de
» Ansprechpartner anzeigen
University clinic, clinical for children and youth
91054 Erlangen
(Bayern)
GermanyAktiv, nicht rekrutierend» Google-Maps
Hautkrebszentrum Universitätsklinikum Erlangen
Ulmenweg 18
91054 Erlangen
(Bayern)
DeutschlandRekrutierend» Google-Maps
Ansprechpartner:
Andreas Mackensen, Prof.Dr.
Phone: 0049 (0)9131 8535 954
E-Mail: andreas.mackensen@uk-erlangen.de

Barbara Ferstl, Dr.
Phone: 0049 (0)9131 8543 104
E-Mail: barbara.ferstl@uk-erlangen.de
» Ansprechpartner anzeigen
University medicine Goettingen, Clinic of hematology and medical oncology
37075 Göttingen
(Niedersachsen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Justin Hasenkamp, Dr.
Phone: +49 55 139 651 82
E-Mail: justin.hasenkamp@med.uni-goettingen.de

Gerald Wulf, Prof., Dr.
Phone: +49 55 139 170 577
E-Mail: gerald.wulf@med.uni-goettingen.de
» Ansprechpartner anzeigen
Children's Hospital of Dr. von Hauner by Ludwig-Maximilian University
80337 Munich
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Tobias Feuchtinger, Prof., Dr.
Phone: +49 89 440 052 759
E-Mail: tobias.feuchtinger@med.uni-muenchen.de

Vera Binder, Dr.
Phone: +49 89 440 052 875
E-Mail: vera.binder@med.uni-muenchen.de
» Ansprechpartner anzeigen
Universitätsklinikum Münster - Klink für Kinderheilkunde und Jugendmedizin / Pädiatrische Hämatologie und Onkologie
48149 Münster
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Claudia Rössig, Prof. Dr.
Phone: 0049 (0)251 83 47 741
E-Mail: rossig@ukmuenster.de

Birgit Burkhardt, PD Dr.
Phone: 0049 (0)251 83 52 840
E-Mail: birgit.burkhardt@ukmuenster.de
» Ansprechpartner anzeigen
Universitätsklinikum Münster - Medizinische Klinik A / KMT Zentrum
48149 Münster
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Matthias Stelljes, Prof. Dr.
Phone: +49 251 83 52801
E-Mail: matthias.stelljes@ukmuenster.de

Jan Henrik Mikesch, Dr.
Phone: +49 251 83 52801
E-Mail: jan-henrik.mikesch@ukmuenster.de
» Ansprechpartner anzeigen
Tuebingen University clinic, medical university clinic for internal medicine
72076 Tuebingen
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Wolfgang Bethge, Prof., Dr.
Phone: +49 70 712 083 176
E-Mail: wolfgang.bethge@med.uni-tuebingen.de

Christoph Faul, Dr.
Phone: +49 70 712 984 087
E-Mail: christoph.faul@med.uni-tuebingen.de
» Ansprechpartner anzeigen
University clinic for children and youth medicine
72076 Tuebingen
(Baden-Württemberg)
GermanyAktiv, nicht rekrutierend» Google-Maps
University clinic, pediatric hematology and oncology
97070 Würzburg
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Paul-Gerhardt Schlegel, Prof., Dr.
Phone: +49 93 120 127 999
E-Mail: schlegel_p@ukw.de

Eyrich Matthias, Prof., Dr.
Phone: +49 93 120 127 620
E-Mail: eyrich_m@ukw.de
» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

The Part I (Phase I) will evaluate the safety of the MB-CART19.1 and determine the

recommended dose levels for the Part II (Phase II) efficacy evaluation in each of the three

disease cohorts.

Dose evaluation will start in Cohorts 1 and 2 with Dose Level 1 and in Cohort 3 with Dose

Level 2, sparing Dose Level 1 (see figure 1). Each of the cohorts will evaluate the safety of

MB-CART19.1.

In each dose level of each of the three cohorts three 3 + 3 patients will be treated. A

particular dose level will be expanded to 6 patients if one patient out of 3 patients treated

at that particular dose level develops DLT. Once this occurs, further dose-escalations are

halted until the dose has proven to be safe in the expanded cohort. If 2 or more in a cohort

of 6 patients develop DLT no further dose escalation is allowed, and the next lower dose

level will be expanded to 6 patients in total. The highest dose among the dose levels tested

at which no more than one out of six patients experiences DLT will be considered the MTD. In

Dose Level 3, three additional patients will be treated, if no DLT occurred. Dose Level 0

will be tested only if Dose Level 1 is not tolerable.

Cohort 3 will Start with Dose Level 2. If Dose Level 2 is not tolerated, Dose Level 1 will be

tested. DLT will be evaluated within 4 weeks after the infusion of MB-CART19.1. An interval

of at least 28 days between the treatment of the first and the second patient in each dose

level (and in each cohort) is mandatory.

Part II (Phase II) will evaluate the efficacy and safety in patients treated with the

recommended dose in Cohorts 1 to 3, respectively. After review of completed day 28 safety and

efficacy data within Part I (Phase I) by the SMB, the design of Phase II, specifically the

number and types of Phase II cohorts and the recommended dose level(s) for Phase II will be

determined and thus, the number of patients to be treated will be calculated.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Male or female patients must have r/r CD19-expressing ALL or NHL/CLL

- CD19 expression must be detected on the malignant cells by flow cytometry (leukemia,

malignant effusion in NHL) or immunohistochemistry (NHL);

- Age ≥ 1 year (if deemed fit by treating investigator);

- Absolute CD3+ T cell count ≥100/μl;

- ECOG performance score of 0-2 if >16 years old, or Lansky performance score of >50 if

≤16 years old at screening;

- No active Hepatitis B, Hepatitis C, HIV1/2;

- No childbearing potential or negative pregnancy test at screening and before

chemotherapy in women with childbearing potential;

- Signed and dated informed consent/assent by patients

- and meet the following disease-specific criteria:

ALL:

- patients with >5% blasts in BM (M2 or M3) after at least one standard chemotherapy and

one salvage regimen who are ineligible for allogeneic stem cell transplant (alloSCT)

or have refractory disease activity precluding alloSCT at this time, or

- patients who have relapsed post alloSCT at least 100 days posttransplant, with no

evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30

days prior to enrollment.

- patients with Ph+ ALL if they are intolerant to tyrosine kinase inhibitor (TKI)

therapy, or if they have r/r disease after treatment with at least 2 different TKIs.

- ALL patients with combined bone marrow and CNS and/or testicular relapse are eligible

only if the extramedullary disease has been successfully cleared by conventional

therapy at the time of inclusion (e.g. intrathecal chemotherapy, orchiectomy).

Pediatric aggressive NHL (1-17 years):

- patients after at least one salvage chemotherapy as bridge to alloSCT or

- patients ineligible for alloSCT or

- patients who have relapsed post alloSCT at least 100 days posttransplant, with not

evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30

days prior to enrollment.

- patients with CNS disease (excluding isolated CNS lymphoma) are eligible only if

disease has been successfully cleared by intrathecal chemotherapy at the time of

inclusion.

Adult NHL:

- patients after at least one standard chemotherapy and one salvage regimen as bridge to

alloSCT or

- patients who are ineligible for alloSCT or

- patients who have relapsed post alloSCT at least 100 days posttransplant, with no

evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30

days prior to enrollment.

- patients with CNS disease (excluding isolated CNS lymphoma) are eligible only if

disease has been successfully cleared by intrathecal chemotherapy at the time of

inclusion.

CLL:

- patients with r/r disease after established and approved treatment options have

failed.

- patients not eligible or appropriate for conventional alloSCT.

Exclusion Criteria:

- Isolated CNS or testicular relapse in ALL;

- Isolated CNS lymphomas;

- Active solid brain metastases or history of solid brain metastases

- Current autoimmune disease, or history of autoimmune disease with potential CNS

involvement;

- Active clinically significant CNS dysfunction (including but not limited to

uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia,

paralysis);

- History of an additional malignancy other than non-melanoma skin cancer or carcinoma

in situ unless disease free for ≥3 years;

- Pulmonary function: Patients with pre-existing severe lung disease or an oxygen

requirement of >28% O2 supplementation or active pulmonary infiltrates on chest X-ray;

- Cardiac function: Fractional shortening <28% or left ventricular ejection fraction

<50% by echocardiography;

- Renal function: GFR ≤29 mL/min/1.73 m2 by CKD-EPI for patients 18 yrs (Levey et al.

2009) or creatinine clearance ≤29 mL/min/1.73 m2 by Schwartz formula (Schwartz et al.

1976) for patients <18 yrs of age;

- Liver function: Patients with a serum bilirubin >3 times upper limit of normal or an

AST or ALT > 5 times upper limit of normal, unless due to leukemic liver infiltration

in the estimation of the investigator;

- Rapidly progressive disease that in the estimation of the investigator would

compromise ability to complete study therapy;

- Pregnant or breast-feeding females;

- Medications:

- Systemic chemotherapies, corticosteroids with the exception of physiologic

replacement dosing, tyrosine kinase inhibitors (TKI) within 7 days prior to

leukapheresis,

- Fludarabine/clofarabine or immunosuppressive drugs and antibodies (e.g.

rituximab, calcineurin inhibitors, blinatumomab) or investigational drugs or

donor lymphocyte transfusions or radiation therapy within 30 days prior to

apheresis,

- Alemtuzumab within 3 months prior to leukapheresis,

- Exception: Intrathecal chemotherapy is allowed prior to treatment, but should be

discontinued in ALL and BL 10 days prior to MB-CART19.1 infusion to limit risk of

neurotoxicities;

- Hypersensitivity against any drug or its ingredients/impurities that is scheduled or

likely to be given during trial participation, e.g. as part of the mandatory

lymphodepletion protocol, pre-medication for infusion, rescue medication/salvage

therapies for treatment related toxicities;

- Intake of concomitant medication contraindicated for other reasons than

hypersensitivity, e.g. live vaccines and fludarabine;

- Contraindication of trial related procedures as judged by the investigator, e.g.

lumbar punctures for CSF sampling;

- Female patients of child-bearing potential not willing to practice a highly effective

form of birth control from the time of enrollment and for 12 months after dosing the

IMP;

- Male patients of fathering potential not willing to practice a highly effective form

of birth control from the time of enrollment and for 12 months after dosing the IMP;

- Concurrent participation in another interventional trial that could interact with this

trial, e.g. CAR T trials;

- Cerebral dysfunction, legal incapacity of adult patients;

- Committal to an institution on judicial or official order.

Studien-Rationale

Primary outcome:

1. Phase I - Determination of the recommended dose of MB-CART19.1 (Time Frame - until day 28 after infusion of MB-CART19.1):
Determined on the basis of the maximum tolerated dose (MTD); MTD is defined as the highest dose level at which < 33% of patients experience Dose Limiting Toxicity (DLT). Safety and toxicity assessment of MB-CART19.1 per adverse events (AE) reporting classified according to CTCAE version 5.0

2. Phase II - Determination of the Overall Response Rate (ORR) (Time Frame - 28 days after infusion of MB-CART19.1 (and at month 3 in NHL patients not in CR on day 28)):
ORR in ALL patients is defined as the rate of complete remission (CR, CRh); ORR in NHL patients is defined as the rate of overall response (CR or PR)

Secondary outcome:

1. Phase I - Overall incidence and severity of adverse events (Time Frame - throug study completion, an average of 5 years):
per adverse events (AE) reporting classified according to CTCAE version 5.0

2. Phase I - Response to treatment for each timepoint (Time Frame - day 28):
ORR in ALL (Rate of CR/CRh)

3. Phase I - Response to treatment for each timepoint (Time Frame - day 28, week 12, month 6, 1 year):
Rate MRD-negative CR in ALL

4. Phase I - Response to treatment for each timepoint (Time Frame - day 28, patients not in CR on day 28: month 3):
ORR in NHL/CLL (Rate of CR/PR)

5. Phase I - Occurence of B-cell depletion (Time Frame - through study completion, an average of 5 years):
Circulating B cell numbers

6. Phase I - Phenotype and persistence of MB-CART19.1 (Time Frame - days 2, 7, 10, 14, 28, weeks 8, 12, months 6, 12, 24, 36, 48, 60):
Blood samples for determination of persistence/phenotyping of infused MB-CART19.1 will be analysed.

7. Phase II - Overall incidence and severity of adverse events (Time Frame - through study completion, an average of 5 years):
per adverse events (AE) reporting classified according to CTCAE version 5.0

8. Phase II - Number of patients with successful MB-CART19.1 production (Time Frame - day 0):
Number of patients meeting the inclusion criteria and none of the exclusion criteria for who an autologous MB-CART19.1 product can be generated

9. Phase II - Rate of ALL patients achieving MRD negative CR (Time Frame - day 28, week 12, month 6, 1 year):
Rate MRD-negative CR in ALL

10. Phase II - Duration of response (Time Frame - through study completion, an average of 5 years):
Determination of response rate

11. Phase II - Disease-free survival (Time Frame - at 1 year after MB-CART19.1 infusion in patients not receiving alloSCT):
Determination of survival and relapse

12. Phase II - Occurrence of B cell depletion (Time Frame - days 7, 10, 14, 28, weeks 8, 12, 16, months 6, 8, 10, 12, 24, 36, 48, 60):
Circulating B cell numbers in the peripheral blood will be assessed by Flow cytometry.

13. Phase II - Phenotype and persistence of MB-CART19.1 (Time Frame - days 2, 7, 10, 14, 28, weeks 8, 12, months 6, 12, 24, 36, 48, 60):
Blood samples for determination of persistence/phenotyping of infused MB-CART19.1 will be analysed.

Studien-Arme

  • Experimental: Phase I: DL 0: 1x10e5 MB-CART19.1 cells
    In each dose level of each of the three cohorts three 3 + 3 patients will be treated. A particular dose level will be expanded to 6 patients if one patient out of 3 patients treated at that particular dose level develops DLT. Once this occurs, further dose-escalations are halted until the dose has proven to be safe in the expanded cohort. If 2 or more in a cohort of 6 patients develop DLT no further dose escalation is allowed, and the next lower dose level will be expanded to 6 patients in total. The highest dose among the dose levels tested at which no more than one out of six patients experiences DLT will be considered the MTD.
  • Experimental: Phase I: DL 1: 5x10e5 MB-CART19.1 cells
    Dose evaluation will start in Cohorts 1 and 2 with Dose Level 1. In each dose level of each of the three cohorts three 3 + 3 patients will be treated. A particular dose level will be expanded to 6 patients if one patient out of 3 patients treated at that particular dose level develops DLT. Once this occurs, further dose-escalations are halted until the dose has proven to be safe in the expanded cohort. If 2 or more in a cohort of 6 patients develop DLT no further dose escalation is allowed, and the next lower dose level will be expanded to 6 patients in total. The highest dose among the dose levels tested at which no more than one out of six patients experiences DLT will be considered the MTD.
  • Experimental: Phase I: DL 2: 1x10e6 MB-CART19.1 cells
    Dose evaluation will start in Cohort 3 with Dose Level 2, sparing Dose Level 1. If Dose Level 2 is not tolerated, Dose Level 1 will be tested. In each dose level of each of the three cohorts three 3 + 3 patients will be treated. A particular dose level will be expanded to 6 patients if one patient out of 3 patients treated at that particular dose level develops DLT. Once this occurs, further dose-escalations are halted until the dose has proven to be safe in the expanded cohort. If 2 or more in a cohort of 6 patients develop DLT no further dose escalation is allowed, and the next lower dose level will be expanded to 6 patients in total. The highest dose among the dose levels tested at which no more than one out of six patients experiences DLT will be considered the MTD.
  • Experimental: Phase I: DL 3: 3x10e6 MB-CART19.1 cells
    In each dose level of each of the three cohorts three 3 + 3 patients will be treated. A particular dose level will be expanded to 6 patients if one patient out of 3 patients treated at that particular dose level develops DLT. Once this occurs, further dose-escalations are halted until the dose has proven to be safe in the expanded cohort. If 2 or more in a cohort of 6 patients develop DLT no further dose escalation is allowed, and the next lower dose level will be expanded to 6 patients in total. The highest dose among the dose levels tested at which no more than one out of six patients experiences DLT will be considered the MTD. In Dose Level 3, three additional patients will be treated, if no DLT occurred. Dose Level 0 will be tested only if Dose Level 1 is not tolerable.
  • Experimental: Phase II - Recommended dose MB-CART19.1
    Phase II will evaluate the efficacy and safety in patients treated with the recommended dose in Cohorts 1 to 3, respectively.

Geprüfte Regime

  • MB-CART19.1 (CD19-targeting CAR T cells / Anti-CD19 CAR T cells / ):
    MB-CART19.1 consists of autologous CD19 Chimeric Antigen Receptor (CAR) transduced CD4/CD8 enriched T cells targeting CD19-positive tumor cells in b cell malignancies

Quelle: ClinicalTrials.gov


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