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

NCT03573700

Description:

SJCAR19 is a research study seeking to evaluate the use of chimeric antigen receptor (CAR) T cell therapy, a type of cellular therapy, for the treatment of pediatric, adolescent and young adult patients with relapsed or refractory CD19+ acute lymphoblastic leukemia (ALL). CAR therapy combines two of the body's basic disease fighters: antibodies and T Cells. For this type of therapy, peripheral (circulating) immune cells are collected and then undergo a manufacturing process to engineer them to more effectively kill cancer cells. The SJCAR19 product will be manufactured at the St. Jude Children's Research Hospital's Good Manufacturing Practice (GMP) facility. The main purpose of this study is to determine: 1. The largest dose of SJCAR19 that is safe to give, 2. How long SJCAR19 cells last in the body, 3. The side effects of SJCAR19, and 4. Whether or not treatment with SJCAR19 is effective in treating people with refractory or relapsed ALL.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of CD19-Specific CAR Engineered Autologous T-Cells for Treatment of Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia
  • Official Title: SJCAR19: A Phase I/II Study Evaluating SJCAR19 (CD19-Specific CAR Engineered Autologous T-Cells) in Pediatric and Young Adult Patients ≤ 21 Years of Age With Relapsed or Refractory CD19+ Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: SJCAR19
  • SECONDARY ID: NCI-2017-01399
  • NCT ID: NCT03573700

Conditions

  • Acute Lymphoblastic Leukemia, in Relapse
  • Acute Lymphoblastic Leukemia, Refractory

Interventions

DrugSynonymsArms
CyclophosphamideCytoxanSJCAR19 Therapy
FludarabineFludaraSJCAR19 Therapy
MesnaMesnexSJCAR19 Therapy
CD19- specific CAR engineered autologous T-cells (SJCAR19 product)SJCAR19 Therapy

Purpose

SJCAR19 is a research study seeking to evaluate the use of chimeric antigen receptor (CAR) T cell therapy, a type of cellular therapy, for the treatment of pediatric, adolescent and young adult patients with relapsed or refractory CD19+ acute lymphoblastic leukemia (ALL). CAR therapy combines two of the body's basic disease fighters: antibodies and T Cells. For this type of therapy, peripheral (circulating) immune cells are collected and then undergo a manufacturing process to engineer them to more effectively kill cancer cells. The SJCAR19 product will be manufactured at the St. Jude Children's Research Hospital's Good Manufacturing Practice (GMP) facility. The main purpose of this study is to determine: 1. The largest dose of SJCAR19 that is safe to give, 2. How long SJCAR19 cells last in the body, 3. The side effects of SJCAR19, and 4. Whether or not treatment with SJCAR19 is effective in treating people with refractory or relapsed ALL.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
SJCAR19 TherapyExperimentalPatients in both the Phase I and Phase II portion of the study will receive lymphodepleting chemotherapy (unless determined by PI that lymphodepletion is not necessary), followed by a single infusion of the patient-derived SJCAR19 cellular product. The most commonly used lymphodepleting chemotherapy regimen will consist of the agents: Fludarabine and Cyclophosphamide. They will also receive Mesna. Dosing of SJCAR19 on the Phase I study will follow a dose escalation schema, with dose changes based on dose-limiting toxicities. In the Phase II study, SJCAR19 dosing with follow the maximum tolerated dose, as determined in the Phase I portion. Cells for infusion are prepared using the CliniMACS System.
  • Cyclophosphamide
  • Fludarabine
  • Mesna
  • CD19- specific CAR engineered autologous T-cells (SJCAR19 product)

Eligibility Criteria

        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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose and Dose-limiting Toxicities
Time Frame:4 weeks post-SJCAR19 infusion
Safety Issue:
Description:The primary objectives for the Phase I study portion are to determine the maximum tolerated dose (MTD) and characterize the safety profile and dose-limiting toxicities (DLTs) of treatment with SJCAR19 in pediatric and young adult patient's ≤ 21 years of age, with relapsed or refractory CD19+ ALL.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

Trial Keywords

  • Leukemia
  • Leukemia, lymphoid
  • Leukemia, B-cell
  • Relapsed
  • Refractory
  • Pediatric
  • Chimeric antigen receptor
  • CAR
  • CAR T cell
  • Anti-CD19
  • CD19

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