The PACMAN-Hu19 Trial: a Study of the Safety and Feasibility of Locally Produced, CD19-targeted and Human CAR T-cell Therapy in Children and Young Adults With Relapsed or Refractory B-cell Malignancies

Inclusion Criteria:

1. 1-45 years of age.
2. Patients with relapsed or refractory CD19+ hematological malignancies including, but not limited to:

   1. B-NHL such as Burkitt lymphoma(BL), de novo or transformed diffuse large B cell lymphoma (DLBCL), lymphoblastic lymphoma (LBL), primary mediastinal B cell lymphoma (PMBCL) or indolent lymphoma types with no access to commercially available CAR T-cell therapy or for whom the current production time for commercially available CAR T-cell therapy is not acceptable based on medical need.

      OR
   2. B-cell precursor ALL failing commercially available CAR T-cell therapy, or for BCP-ALL indications with no access to commercially available CAR T-cell therapy, or for whom the current production time for commercially available CAR T-cell therapy is not acceptable based on urgent medical need (the latter needs to be confirmed by the sponsor).
3. Measurable disease:

   1. For B-NHL at least one measurable lesion according to the Lugano classification.
   2. For BCP-ALL at least 0.1% (=10-3) of blasts should be present in the bone marrow measured by molecular MRD, morphology or flow cytometry at screening.
4. Patients must have exhausted or are ineligible for all registered therapeutic options with curative potential.
5. Adequate performance score:

   1. Children \<16 years: Lansky performance status ≥ 60 .
   2. Children age ≥16 years and \<18 years Karnofsky performance status ≥ 60.
   3. Adults ≥18 years ECOG performance status 0, 1 or 2 (ECOG performance status 3 is allowed only when due to underlying disease).
6. Patients from childbearing potential must be willing and able to use highly effective methods of birth control from first chemotherapy infusion through 12 months after administering the last study treatment.
7. Patients must be willing to abstain from breast feeding through 12 months after administering the last study treatment.
8. Patients must agree to refrain from donating blood or organs following treatment with huCAR19 T-cells.
9. Written informed consent per local law and regulations.

   Additional inclusion criteria phase I part of the study:
10. The first three patients in the phase I part of the study must be aged 12-45 years, thereafter patients of any age between 1-45 years can be recruited once surrogate endpoint of BCA is reached in ≥60% patients in previous or current dose level and ≤1 DLT occurred at the previous dose level.

Exclusion Criteria:

1. Patients with symptomatic CNS involvement will be excluded. After resolution and control of symptoms, patients can be rescreened.
2. Active uncontrolled or life-threatening infections.
3. Infection with HTLV-1, HTLV-2, HIV-1, HIV-2, hepatitis B (HbsAg positive) or hepatitis C (anti-HCV positive). Chronic controlled hepatitis B or C infection with undetectable viral load or controlled HIV infection with viral load \<50 IU/ml and CD4+ T-cell count \>200/ml may be considered when antiviral prophylaxis or therapy can be administered.
4. Absolute neutrophil count \<0.5x109/L unless caused by underlying disease.
5. Platelet count \<25x109/L unless caused by underlying disease.
6. Bilirubin and/or transaminases ≤ 2.5 x ULN, unless caused by underlying disease.
7. Renal insufficiency, defined as:

   1. For adults (≥18 years) glomerular filtration rate (GFR) \< 45 ml/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease (MDRD) equation:

      predicted GFR (ml/min/1.73 m2) = 186 x (serum creatinine in umol/L / 88.7) - 1.154 x (age in years) - 0.203 x (0.742 if patient is female) x (1.212 if patient is black).
   2. For children (\<18 years) a serum creatinine based on gender/age as follows (in µmol/l):

   Age Male Female 0 to \< 2 years 53 70 2 to \< 6 years 70 70 6 to \< 10 years 88 88 10 to \< 13 years 106 106 13 to \< 16 years 132 123 16 to \< 19 years 150 123
8. Inadequate pulmonary function defined as baseline oxygen saturation \<92%, if not caused by underlying disease.
9. Inadequate cardiac function:

   1. Unstable angina or unstable cardiac arrhythmias.
   2. NYHA classification \>II.
   3. LVSF \<28% or LVEF \<45% confirmed by echocardiogram or MUGA scan.
10. Concurrent malignancy requiring treatment of having been treated \<3 months before screening except for curatively treated basal cell carcinoma of the skin.
11. Pregnant women.
12. Patients unable to participate in the study according to investigator judgement.
13. Patients not willing or unable to adhere to protocol guidelines or follow-up.
14. Treatment with allogeneic stem cell transplantation \<12 weeks from screening or DLI \<4 weeks from screening or active GVHD requiring systemic treatment. Cutaneous GVHD requiring only topical steroids is allowed.
15. Hypersensitivity to the active substance