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

In this study patients aged 1-45 years with relapsed or refractory CD19+ hematological malignancies (B-NHL or BCP-ALL) are treated with a single dose of huCAR19 T-cells. After consent and screening, patients will undergo leukapheresis to harvest autologous PBMCs. During the CAR T-cell production, patients receive lymphodepleting chemotherapy after which the huCAR19 T-cells are administered. In phase I the aim is to establish the RP2D, the protocol will then be extended to a phase II.

Inclusion criteria

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

• 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

• 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).
• Measurable disease:

• For B-NHL at least one measurable lesion according to the Lugano classification.
• 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.
• Patients must have exhausted or are ineligible for all registered therapeutic options with curative potential.
• Adequate performance score:

• Children <16 years: Lansky performance status ≥ 60 .
• Children age ≥16 years and <18 years Karnofsky performance status ≥ 60.
• Adults ≥18 years ECOG performance status 0, 1 or 2 (ECOG performance status 3 is allowed only when due to underlying disease).
• 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.
• Patients must be willing to abstain from breast feeding through 12 months after administering the last study treatment.
• Patients must agree to refrain from donating blood or organs following treatment with huCAR19 T-cells.
• Written informed consent per local law and regulations.

Additional inclusion criteria phase I part of the study:

• 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

• Patients with symptomatic CNS involvement will be excluded. After resolution and control of symptoms, patients can be rescreened.
• Active uncontrolled or life-threatening infections.
• 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.
• Absolute neutrophil count <0.5x109/L unless caused by underlying disease.
• Platelet count <25x109/L unless caused by underlying disease.
• Bilirubin and/or transaminases ≤ 2.5 x ULN, unless caused by underlying disease.
• Renal insufficiency, defined as:

• 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).

• 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

• Inadequate pulmonary function defined as baseline oxygen saturation <92%, if not caused by underlying disease.
• Inadequate cardiac function:

• Unstable angina or unstable cardiac arrhythmias.
• NYHA classification >II.
• LVSF <28% or LVEF <45% confirmed by echocardiogram or MUGA scan.
• Concurrent malignancy requiring treatment of having been treated <3 months before screening except for curatively treated basal cell carcinoma of the skin.
• Pregnant women.
• Patients unable to participate in the study according to investigator judgement.
• Patients not willing or unable to adhere to protocol guidelines or follow-up.
• 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.
• Hypersensitivity to the active substance