Evaluation of CD19-Specific CAR Engineered Autologous T-Cells for Treatment of Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia

SJCAR19 is a Phase I/II clinical trial evaluating the use of SJCAR19 (CD19- specific CAR engineered autologous T-cells) in pediatric, adolescent and young adult patients with relapsed/ refractory CD19+ ALL. Treatment will include a single treatment course, with most patients receiving a lymphodepleting chemotherapy preparative regimen of fludarabine/ cyclophosphamide, followed by a single infusion of SJCAR19.

This protocol contains a 3-part consent process: 1) to proceed with autologous apheresis, 2) to proceed with manufacturing of the SJCAR19 product, and 3) to receive treatment with the SJCAR19 product (initially as Phase I, then proceeding to Phase II). The Phase I portion will evaluate the safety and maximum tolerated dose (MTD) of SJCAR19.

The Phase II portion will evaluate the efficacy, and provide further safety evaluation, of SJCAR19 in an expansion cohort at the MTD determined in the Phase I portion of the study. Additionally, for both the Phase I/II portions of the study there are correlative studies evaluating the biology of this treatment as well assessments into patient/caregiver experiences with undergoing this treatment.

Inclusion criteria

for Autologous Apheresis:

• Age ≤ 21 years old
• CD19+ ALL with any of the following:

• Minimal Residual Disease (MRD) ≥ 1% at end of up-front induction therapy
• Hypodiploid (< 44 chromosomes or < 0.95 DNA index) CD19+ ALL with detectable disease at the end of up-front induction therapy
• Increase in disease burden any time after the completion of up-front induction therapy
• Primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission
• Refractory disease despite salvage therapy
• 1st or greater relapse
• Estimated life expectancy of > 12 weeks
• Karnofsky or Lansky (age-dependent) performance score ≥ 50
• Patients with a history of prior allogeneic hematopoietic cell transplantation [HCT] must be clinically recovered from prior HCT therapy, have no evidence of active GVHD and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to apheresis
• For females of child bearing age:

• Not lactating with intent to breastfeed
• Not pregnant with negative serum pregnancy test within 7 days prior to enrollment

Exclusion criteria

for Autologous Apheresis:

• Known primary immunodeficiency
• History of HIV infection
• Severe intercurrent bacterial, viral or fungal infection
• History of hypersensitivity reactions to murine protein-containing products

Eligibility Criteria for Manufacturing SJCAR19:

• CD19+ ALL with any of the following:

• Primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission
• Refractory disease despite salvage therapy
• 2nd or greater relapse
• Any relapse after allogeneic hematopoietic cell transplantation
• 1st relapse if patient requires an allogeneic HCT as part of standard of care relapse therapy, but is found to be ineligible and/or unsuitable for HCT
• Age: ≤ 21 years of age
• Karnofsky or Lansky (age-dependent) performance score ≥ 50
• Estimated life expectancy of > 12 weeks
• Meets eligibility criteria to undergo autologous apheresis, or have previously undergone autologous apheresis

Inclusion criteria

for Treatment with SJCAR19:

• CD19+ ALL with any of the following:

• Primary refractory disease despite at least 2 cycles of an intensive chemotherapy regimen designed to induce remission
• Refractory disease despite salvage therapy
• 2nd or greater relapse
• Any relapse after allogeneic hematopoietic cell transplantation
• 1st relapse if patient requires an allogeneic HCT as part of standard of care relapse therapy, but is found to be ineligible and/or unsuitable for HCT for any of the following reasons:

• Patients that do not have an available allogeneic donor (defined as at least a 7/8 HLA-matched related/unrelated donor, 5/6 HLA-matched umbilical cord donor, or 3/6 HLA-matched haploidentical donor)
• Patients with refractory leukemia, for which allogeneic transplant is known to be less effective in the B-ALL population, and
• Patients who are unable to receive myeloablative total body irradiation (TBI), which is included in standard transplant regimens for patients with B - ALL.
• Detectable disease
• Age: ≤ 21 years of age
• Estimated life expectancy of > 8 weeks
• Prior to planned SJCAR19 infusion, patients with a history of prior allogeneic HCT must be at least 3 months from HCT, have no evidence of active GVHD and have not received a donor lymphocyte infusion (DLI) within the 28 days prior to planned infusion
• Adequate cardiac function defined as left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%
• EKG without evidence of clinically significant arrhythmia
• Adequate renal function defined as creatinine clearance or radioisotope GFR ≥50 ml/min/1.73m2 (GFR ≥40 ml/min/1.73m2 if < 2 years of age)
• Adequate pulmonary function defined as forced vital capacity (FVC) ≥ 50% of predicted value; or pulse oximetry ≥ 92% on room air if patient is unable to perform pulmonary function testing
• Karnofsky or Lansky (age-dependent) performance score ≥ 50
• Total Bilirubin ≤ 3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 times the upper limit of normal for age
• Hemoglobin > 8 g/dl (can be transfused)
• Platelet count > 20,000/μL (can be transfused)
• Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy
• For females of child bearing age:

• Not lactating with intent to breastfeed
• Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
• If sexually active, agreement to use birth control until 6 months after T-cell infusion. Male partners should use a condom
• Available SJCAR19 product with ≥ 15% expression of the CD19-CAR, and killing of CD19+ targets ≥ 20% in an in vitro cytotoxicity assay
• Agreement to participate in long-term follow-up on protocol NCT00695279

Exclusion criteria

for Treatment with SJCAR19:

• CNS-3 disease with or without neurologic changes
• CNS-1/CNS-2 disease with neurologic changes
• Known primary immunodeficiency
• History of HIV infection
• Evidence of active, uncontrolled neurologic disease
• Severe, uncontrolled bacterial, viral or fungal infection
• History of hypersensitivity reactions to murine protein-containing products
• Receiving systemic steroids therapy exceeding the equivalent of 0.5 mg/ kg/day of methylprednisolone, in the 7 days prior to CAR T-cell infusion
• Receiving systemic immunosuppressive therapy in the 14 days prior to CAR T-cell infusion
• Receiving intrathecal chemotherapy in the 7 days prior to CAR T-cell infusion