CART19 Cells Effects in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma

Safety and Efficacy of Anti-CD19 Chimeric Antigen Receptor-modified Autologous T Cells (CART19) in Patients with Relapsed/refractory CD19+ Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma. a Dose Escalation, Open-label, Phase I Study.

Phase I Dose Escalation Study of CART19 Cells for Adult Patients With Relapsed / Refractory Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma.

This is an open-label, single arm study on up to 24 adult subjects with refractory or relapsed CD19+ Non-Hodgkin's Lymphoma or B-ALL. Following lymphodepleting conditioning regimen, the patients will receive a single dose of autologous CAR19 T lymphocytes provided by the sponsor´s manufacturing facility. CART19 dose will be escalated in consecutive patients using accelerated titration design in order to establish recommended CART19 dose for further study, which will be either Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD), whichever is reached first.

Inclusion Criteria:

1. Patient with refractory or relapsing CD19 positive B-ALL or B-NHL defined as:

   1. B-ALL refractory to treatment or in the second or subsequent relapse (hematological OR molecular), OR
   2. B-NHL refractory to treatment or in first relapse ineligible for autologous stem cell transplantation (ASCT) or in second to fourth relapse, OR
   3. B-ALL or B-NHL relapsing after autologous or allogeneic hematopoietic cell transplantation (HCT).

2. CD19 expression on malignant cells confirmed by flow cytometry or by immunohistochemistry.

3. Age ≥18 years and ≤ 80 yearss.

4. Patient able to understand and sign informed consent.

5. Women of child-bearing potential: negative pregnancy test at enrolment (PSV) and at Visit 1.

General Exclusion Criteria:

1. Known hypersensitivity to any component of the Investigational Medicinal Product (IMP).

2. Autologous or allogeneic HCT in 3 months prior to IMP administration.

3. Severe, uncontrolled active infection.

4. Life expectancy < 6 weeks.

5. Parenchymal central nervous system involvement.

6. Respiratory insufficiency (need for oxygen therapy).

7. Significant liver impairment: bilirubin > 50 µmol/L, AST or ALT > 4times normal upper limit.

8. Acute kidney injury with serum creatinine > 180 µmol/L, oliguria or need for acute dialysis.

9. Heart failure with EF < 30% by echocardiography.

10. Presence of active grade 3-4 acute GvHD.

11. Serious uncontrolled neurological comorbidity.

12. Vaccination with live virus vaccines in the 4 weeks before IMP administration and within 90 days after the IMP dose.

13. Women: pregnancy or breast-feeding.

14. Subjects of fertile age, unless permanent sexual abstinence is their lifestyle choice:

    • female patients of childbearing potential not willing to use a highly effective method of contraception during the study,
    • male patients whose sexual partner(s) are women of childbearing potential who are not willing to use a highly effective method of contraception during the study.

Exclusion criteria to Procurement of IMP manufacture starting material

1. Severe uncontrolled active infection.

2. Positive test results for HIV1/2, Hepatitis B/C and lues.

3. Concurrent or recent prior therapies before apheresis:

   • Autologous or allogeneic hematopoietic cell transplantation within 12 weeks.
   • Clofarabine, Fludarabine, Alemtuzumab within 8 weeks.
   • Donor lymphocyte infusions within 4 weeks.
   • Pegylated asparaginase within 4 weeks.
   • Maintenance chemotherapy within 2 weeks.
   • Long-acting Granulocyte Colony Stimulating Factor (G-CSF) within 2 weeks.
   • Vincristine within 2 weeks.
   • Intrathecal methotrexate within 1 week.
   • Granulocyte Colony Stimulating Factor (G-CSF) within 5 days.
   • Therapeutic dose of corticosteroids within 3 days.
   • Short-acting cytostatics within 3 days

Exclusion criteria to IMP administration

1. Severe, uncontrolled active infections.
2. Life expectancy < 6 weeks.
3. Parenchymal central nervous system involvement
4. Respiratory insufficiency (need for oxygen therapy).
5. Significant liver impairment: bilirubin > 50 µmol/L, Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 4times normal upper limit.
6. Acute kidney injury with serum creatinine > 180 µg/L, oliguria or need for acute dialysis.
7. Heart failure with Ejection Fraction (EF) < 30% by echocardiography.
8. Presence of active grade 3 - 4 acute GvHD
9. Serious uncontrolled neurological comorbidity.