Finding the right dose of MB-CART2219.1 CAR‑T (targets CD19 and CD22) for relapsed B‑cell cancers

Inclusion Criteria:

1. For Cohort I Lymphoma, adults: Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. For Cohort II ALL, pediatric patients: Subject is ≥ 12-17 years of age at the time of signing ICF.
3. Patient or legal guardian understand and voluntarily sign an informed consent document prior to any study related assessments/procedures.
4. Able to adhere to the study visit schedule and other protocol requirements as well as agrees to continued follow up for up to 15 years as mandated by the regulatory guidelines for gene therapy trials.
5. CD19 or CD22 expression must be detected on the malignant cells by flow cytometry or immunohistochemistry. 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.
6. Female Subject of childbearing potential and male subjects with female partner of childbearing potential is willing to use highly effective contraceptive methods during treatment until 12 months after IMP exposure.
7. All subjects must agree to refrain from donating blood while on study drug and for 1 year after discontinuation from this study treatment.
8. Male or female patients must have relapsed refractory (r/r) CD19 or CD22 -expressing ALL or Lymphoma/CLL and meet the following disease-specific criteria.

Cohort I: Lymphoma (Richter's Transformation /Burkitt lymphoma/NHL/CLL), Adults ≥18 years of age:

* Disease entities: Patients with relapsed or refractory (r/r) B-cell lymphoid malignancies according to the WHO Classification of Haematolymphoid Tumours (5th edition), including:

  * B-lymphoblastic lymphoma
  * Chronic lymphocytic leukemia (CLL)
  * Splenic B-cell lymphoma
  * Marginal zone lymphoma
  * Follicular lymphoma
  * Mantle cell lymphoma
  * Diffuse large B-cell lymphoma (DLBCL) / Large B-cell lymphoma
  * Burkitt lymphoma
  * Transformed indolent B-cell lymphoma (including Richter's transformation)
* Prior treatment and disease status: Patients must meet one of the following criteria:

  1. Relapsed or refractory disease after ≥2 prior systemic therapies, including at least one of the following (if clinically indicated and available):

     * Approved CAR-T cell therapy, or
     * Bispecific antibody therapy OR
  2. Contraindication to CAR-T cell therapy and/or bispecific antibody therapy
* CLL-specific: Patients with relapsed or refractory CLL:

  * After failure of established and approved treatment options
  * Including prior exposure to BTK inhibitor-based therapy
* Transplant-related eligibility: Patients fulfilling at least one of the following:

  1. Indication for autologous or allogeneic stem cell transplantation (SCT) as determined by a multidisciplinary board, but ineligible for SCT, or declining SCT after informed consent discussion
  2. Patients with refractory disease currently precluding alloSCT, including those considered for bridging to allogeneic SCT within the study framework
* Post-transplant or post-targeted therapy relapse: Patients meeting at least one of the following:

  1. Relapse following autologous or allogeneic SCT
  2. Relapse following CD19- or CD22-directed therapy
  3. Confirmed expression of CD19 or CD22 at relapse
* Central nervous system (CNS) involvement

  1. Patients with CNS involvement by lymphoma are eligible
  2. Provided that CNS disease is adequately controlled at the time of study inclusion Or

Cohort II: Acute B-lymphoplastic Leukemia (B-ALL), pediatric patients aged ≥ 12 - 17 years:

* Patients with second or later relapse of ALL with \>5% blasts in BM or rising molecular failure on two separate measurements and without an approved option for in label CAR-T cells or bispecific or cytotoxic antibody treatment.
* Patients with relapse after SCT or other CD19 or CD22 targeted treatment with confirmed either CD19 or CD22 expression after relapse.
* Patients not consenting or ineligible for allogeneic SCT or have refractory disease activity precluding allogemeoc SCT at this time, or
* 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 controlled by conventional therapy at the time of inclusion (e.g. intrathecal chemotherapy, orchiectomy).
* Patients with ALL in hematologic remission after induction treatment, but ineligible for full execution of further standardly recommended treatments because of medical or other reasons.

Exclusion Criteria:

1. Subject received any of the following within the last 7 days of leukapheresis:

   * Any investigational agent
   * Immunsupressive medication
   * Plasmapheresis
   * Major surgery (as defined by the investigator)
   * Radiation therapy other than local therapy for underlying malignancy
   * Use of any systemic anti-neoplastic drug therapy or immune suppressive medication applied for graft versus-host-disease or other, including the use of high dose steroids e.g. \>0,5 mg/kg BW methylprednisolone other than hydrocortisone replacement and other than intermittent topical, inhaled or intranasal corticosteroids which are allowed
2. Subject has ECOG ≥ 3 at screening for inclusion in the trial
3. Subject has clinical evidence of pulmonary leukostasis, disseminated intravascular coagulation or active graft versus-host-disease
4. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, subarachnoid hemorrhage or other CNS bleed, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis
5. Subject has any of the following laboratory abnormalities:

   * Absolute neutrophil count (ANC) \< 500/μL
   * Platelet count \< 50,000 mm3 (platelet transfusion allowed)
   * Serum Creatinine Clearance (CrCl) \< 30 mL/min
   * Corrected serum calcium \> 13.5 mg/dL (\> 3.4 mmol/L)
   * Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 × upper limit of normal (ULN)
   * Serum total bilirubin \> 1.5 × ULN or \> 3.0 mg/dL for subjects with documented Gilbert's syndrome or if part of disease involvement
   * International ratio (INR) or partial thromboplastin time (PTT) \> 1.5 × ULN, or history of Grade ≥ 2 hemorrhage within 30 days, or subject requires ongoing treatment with chronic, therapeutic dosing of anticoagulants (eg, warfarin, low molecular weight heparin, Factor Xa inhibitors)
6. Patient has no adequate vascular access for leukapheresis
7. Echocardiogram (ECHO) or multi-gated acquisition (MUGA) with left ventricular ejection fraction \< 40%
8. Patient with a history of Class III or IV congestive heart failure (CHF) or severe nonischemic cardiomyopathy, unstable or poorly controlled angina, myocardial infarction, or ventricular arrhythmia within the previous 3 months prior to starting study treatment
9. Inadequate pulmonary function defined as oxygen saturation (Sa02) \< 90 % on room air
10. Subject has history of primary immunodeficiency
11. Subject is positive for human immunodeficiency virus (HIV-1), uncontrolled hepatitis B or C or active hepatitis A
12. Subject with ongoing (incl. controlled) infections or infestations where inclusion of the patient into the clinical trials may significantly jeopardize the health and wellbeing of the patient, as determined by the investigator.
13. Subject with malignancy other than the underlying malignancy in this protocol, unless this disease has been controlled for ≥ 1 year and the exception of the following noninvasive malignancies:

    * Basal cell carcinoma of the skin
    * Squamous cell carcinoma of the skin
    * Carcinoma in situ of the cervix
    * Carcinoma in situ of the breast
    * Incidental histologic finding of prostate cancer (T1a or T1b using the TNM \[tumor, nodes, metastasis\] clinical staging system) or prostate cancer that is curative
14. Patient is a female who is pregnant, nursing, or breastfeeding, or who intends to become pregnant during participation in the study
15. Patient with known hypersensitivity to any component of MB-CART2219.1 product, cyclophosphamide, fludarabine, and/or tocilizumab
16. Patient has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
17. Patient has any further condition including the presence of further laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study