Treatment for relapsed or refractory CD19-positive B-cell malignancies

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

This study is testing a new treatment called MB-CART19.1 to see if it can safely help people, both adults and children, with tough-to-treat CD19-positive B-cell cancers like leukemia and lymphoma.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 48 (estimated)
• Ages: 1 Year and up
• Sex: All
• Sponsor: Miltenyi Biomedicine GmbH (Industry-sponsored)
• Drugs / interventions: rituximab, blinatumomab, Alemtuzumab, CAR T, chemotherapy, radiation, Fludarabine
• Locations: 11 sites (Berlin and 10 other locations)
• Trial ID: NCT03853616 on ClinicalTrials.gov

What this trial studies

This clinical trial is a phase I/II, multi-center, single-arm, prospective study evaluating the safety and efficacy of MB-CART19.1 in patients with relapsed or refractory CD19-positive B-cell malignancies, including acute lymphoblastic leukemia and B-cell lymphoma. The trial consists of two parts: Part I focuses on dose escalation to determine the maximum tolerated dose (MTD) across three cohorts defined by disease type. Each cohort will treat a specific group of patients, including both adults and children, to assess the safety of the treatment before moving on to efficacy evaluation in Part II.

Who should consider this trial

Good fit: Ideal candidates include patients aged 1 year and older with relapsed or refractory CD19-expressing B-cell malignancies who are ineligible for allogeneic stem cell transplant.

Not a fit: Patients with active viral infections such as Hepatitis B, Hepatitis C, or HIV, or those who do not express CD19 on their malignant cells will not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with difficult-to-treat B-cell malignancies.

How similar studies have performed: Other studies have shown promising results with similar CAR T-cell therapies targeting CD19, indicating potential for success in this approach.

Eligibility criteria

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.

Where this trial is running

Berlin and 10 other locations

• Charité - University clinic, pediatric clinic with focus on oncology and hematology — Berlin, Germany (Recruiting)
• Charite - Medical Clinic with focus on hematology, oncology and tumor immunology — Berlin, Germany (Withdrawn)
• University clinic, clinical for children and youth — Erlangen, Germany (Withdrawn)
• Universitätsklinikum Erlangen — Erlangen, Germany (Recruiting)
• University medicine Goettingen, Clinic of hematology and medical oncology — Göttingen, Germany (Recruiting)
• Children's Hospital of Dr. von Hauner by Ludwig-Maximilian University — Munich, Germany (Recruiting)
• Universitätsklinikum Münster - Klink für Kinderheilkunde und Jugendmedizin / Pädiatrische Hämatologie und Onkologie — Münster, Germany (Recruiting)
• Universitätsklinikum Münster - Medizinische Klinik A / KMT Zentrum — Münster, Germany (Recruiting)
• Tuebingen University clinic, medical university clinic for internal medicine — Tuebingen, Germany (Recruiting)
• University clinic for children and youth medicine — Tuebingen, Germany (Active_not_recruiting)
• University clinic, pediatric hematology and oncology — Würzburg, Germany (Completed)

Study contacts

• Principal investigator: Claudia Rössig, Prof. Dr. — Univeristy Hospital Muenster
• Study coordinator: Clinical Trial Manager

Conditions Acute Lymphoblastic Leukemia Recurrent; B-cell Lymphoma Recurrent; B-cell Lymphoma Refractory; Chronic Lymphocytic Leukemia Recurrent; Chronic Lymphocytic Leukemia Refractory