MB-CART19.1 r/r CD19+ BCM

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Miltenyi Biomedicine GmbH

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15], Diseases [C] - Neoplasms [C04]

Trial duration

15 May 2018 → ongoing

Decision date (initial)

2024-09-17

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Miltenyi Biomedicine GmbH

External identifiers

EU CT number

2024-513334-38-00

EudraCT number

2017-002848-32

ClinicalTrials.gov

NCT03853616

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Dose response, Therapy, Efficacy, Safety

The objective of this trial is to assess feasibility, safety and efficacy of ex vivo generated MB-CART19.1 in patients with relapsed or refractory CD19 positive B cell malignancies.

Primary objective: To determine the recommended dose of MB-CART19.1.

Secondary objectives 3

1. Preliminary evidence of response to MB-CART 19.1 treatment;
2. Phenotype and persistence of MB-CART19.1.
3. To determine duration of response, relapse rate, disease-free and overall survival after treatment with MB-CART19.1

Conditions and MedDRA coding

Refractory/relapsed B-NHL

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male or female patients must have r/r CD19-expressing ALL or NHL/CLL and meet the following disease-specific criteria: All Cohorts: 1a) 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 1b) patients who have relapsed post alloSCT no earlier than 100 days posttransplant, with no evidence of active GVHD, and not taking immunosuppressive agents for at least 30 days prior to leukapheresis. 1c) 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. 1d) 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): 1e) patients after at least one salvage chemotherapy as bridge to alloSCT or 1f) patients ineligible for alloSCT or 1g) patients who have relapsed post alloSCT no earlier than 100 days posttransplant, with not evidence of active GVHD, and not taking immunosuppressive agents for at least 30 days prior to leukapheresis. 1h) 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: 1i) patients after at least one standard chemotherapy and one salvage regimen as bridge to alloSCT or 1j) patients who are ineligible for alloSCT or 1k) patients who have relapsed post alloSCT no earlier than 100 days posttransplant, with no evidence of active GVHD, and not taking immunosuppressive agents for at least 30 days prior to leukapheresis. 1l) 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: 1m) patients with r/r disease after established and approved treatment options have failed. 1n) 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 parents, before conduct of any trial-specific procedure.

Exclusion criteria 15

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
11. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Recommended dose of MB-CART19.1, determined on the basis of the maximum tolerated dose (MTD), defined as the highest dose level of the two to three dose levels tested at which <33% of patients experience DLT until day 28 after infusion of MB-CART19.1, and on the basis of the safety and efficacy data.
2. Safety and toxicity assessment of MB-CART19.1 per adverse events (AE) reporting classified according to CTCAE version 5.0. defined by <33% of patients experiencing DLT, or maximal administered dose.

Secondary endpoints 9

1. Overall incidence and severity of adverse events
2. Response to treatment: o Overall response rate (ORR) in ALL patients defined as the rate of complete remission (CR, CRh) on day 28; o Rate of ALL patients achieving MRD response (<10-4); o ORR in NHL patients is defined as the rate of overall response (CR or PR) on day 28 and at month 3 in patients not in CR on day 28
3. Occurrence of B cell depletion
4. Phenotype and persistence of MB-CART19.1
5. Further safety assessments.
6. Proportion of patients meeting the inclusion criteria and none of the exclusion criteria for who an autologous MB-CART19.1 product can be generated;
7. Rate of ALL patients achieving MRD response (<10-4)
8. Duration of response, relapse rate and time to relapse;
9. Disease-free and overall survival at 1 year after adoptive immunotherapy with MB-CART19.1 in patients not receiving alloSCT;

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Miltenyi Biomedicine GmbH

Sponsor organisation

Miltenyi Biomedicine GmbH

Address

Friedrich-Ebert-Strasse 68, Moitzfeld Moitzfeld

City

Bergisch Gladbach

Postcode

51429

Country

Germany

Scientific contact point

Organisation

Miltenyi Biomedicine GmbH

Contact name

Clinical Trial Desk

Public contact point

Organisation

Miltenyi Biomedicine GmbH

Contact name

Clinical Trial Desk

Third parties 12

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications