A phase I/II safety, dose finding and feasibility trial of MB-CART19.1 in patients with relapsed or refractory CD19 positive B cell malignancies.

Phase 1

• Conditions: Pediatric and adult patients with relapsed/refractory (r/r) CD19-expressing B cell acute lymphoblastic leukemia (ALL) and Non-Hodgkin lymphoma (NHL), including chronic lymphocytic leukemia (CLL).; MedDRA version: 21.0Level: LLTClassification code 10063625Term: Acute lymphoblastic leukemia recurrentSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: PTClassification code 10003902Term: B-cell lymphoma recurrentSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: PTClassification code 10003903Term: B-cell lymphoma refractorySystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: LLTClassification code 10008977Term: Chronic lymphocytic leukemia recurrentSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.1Level: LLTClassification code 10008978Term: Chronic lymphocytic leukemia refractorySystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-002848-32-DE
• Lead Sponsor: Miltenyi Biomedicine GmbH

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2017-10-02
• Last Update Posted: 22 April 2024

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

1. Male or female patients must have r/r CD19-expressing ALL or NHL and meet the following disease-specific criteria:

ALL:
a 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
b patients who have relapsed post alloSCT at least 100 days post-transplant, with no evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to leukapheresis.
c 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.
d 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):
e patients after at least one salvage chemotherapy as bridge to alloSCT or
f patients ineligible for alloSCT or
g patients who have relapsed post alloSCT at least 100 days post-transplant, with not evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to leukapheresis.
h 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:
i patients after at least one standard chemotherapy and one salvage regimen as bridge to alloSCT or
j patients who are ineligible for alloSCT or
k patients who have relapsed post alloSCT at least 100 days post-transplant, with no evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to leukapheresis.
l 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:
m patients with r/r disease after established and approved treatment options have failed.
n patients not eligible or appropriate for conventional alloSCT

2. CD19 expression must be detected on the malignant cells by flow cytometry (leukemia, malignant effusion in NHL) or immunohistochemistry (NHL); Results of previous assessments after the last treatment with CD19 targeted therapies but preceding inclusion of the patient in this trial are acceptable, if available;
3. Age =1 year (if deemed fit by treating investigator);
4. Absolute CD3+ T cell count =100/µl;
5. ECOG performance score of 0-2 if >16 years old, or Lansky performance score of >50 if =16 years old at screening;
6. No active Hepatitis B, Hepatitis C, HIV1/2;
7. No childbearing potential or negative pregnancy test at screening and before chemotherapy in women with childbearing potential;
8. Signed and dated informed consent/assent by patients and/or, in case of patients <18 years by parents, before conduct of any trial-specific procedure.

Are the trial subjects under 18? yes
Number of subjects for this age range: 18
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 13
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 17

Exclusion Criteria

1. Isolated CNS or testicular relapse in ALL;
2. Isolated CNS lymphomas;
3. Active solid brain metastases or history of solid brain metastases
4. Current autoimmune disease, or history of autoimmune disease with potential CNS involvement;
5. Active clinically significant CNS dysfunction (including but not limited to uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia, paralysis);
6. History of an additional malignancy other than non-melanoma skin cancer or carcinoma in situ unless disease free for =3 years;
7. BMI = 30
8. 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;
9. Cardiac function: Pediatric patients: Fractional shortening <28% or left ventricular ejection fraction <50% by echocardiography, adult patients: left ventricular ejection fraction <50% by echocardiography;
10. 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;10. 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;
12. Rapidly progressive disease that in the estimation of the investigator would compromise ability to complete study therapy;
13. Pregnant or breast-feeding females;
14. Medications:
a Systemic chemotherapies, corticosteroids with the exception of physiologic replacement dosing, tyrosine kinase inhibitors (TKI) and other kinase inhibitors (e.g. ibrutinib) within 7 days prior to leukapheresis,
b. Fludarabine/clofarabine or immunosuppressive drugs and antibodies (e.g. rituximab, calcineurin inhibitors, blinatumomab) or donor lymphocyte transfusions or radiation therapy within 14 days prior to leukapheresis,
c Previous treatment with CAR T cells (e.g. Kymriah®)
d Alemtuzumab within 3 months prior to leukapheresis,
e Exception: Intrathecal chemotherapy is allowed until 8 days prior to leukapheresis, with the exception of cytarabine. After leukapheresis, a single dose of intrathecal chemotherapy is allowed but should be discontinued 10 days prior to MB-CART19.1 infusion to limit risk of neurotoxicities;
15. 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;
16. Intake of concomitant medication contraindicated for other reasons than hypersensitivity within 30 days prior to leukapheresis, e.g. live vaccines and fludarabine
17. Contraindication of trial related procedures as judged by the investigator, e.g. lumbar punctures for CSF sampling;
18. Female patients of child-bearing potential not willing to practice a highly effective form of birth control from the time of leukapheresis and for 12 months after dosing the IMP;
19. 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;
20. Concurrent participation in another interventional trial that could interact with this trial, e.g. CAR T trials;
21. Other investigational treatment within 4 weeks before I

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified