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

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ClinicalTrials.gov Identifier: NCT03573700
Recruitment Status : Recruiting
First Posted : June 29, 2018
Last Update Posted : November 9, 2018
Sponsor:
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Tracking Information
First Submitted Date  ICMJE June 20, 2018
First Posted Date  ICMJE June 29, 2018
Last Update Posted Date November 9, 2018
Actual Study Start Date  ICMJE July 24, 2018
Estimated Primary Completion Date July 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 20, 2018)
  • Maximum Tolerated Dose and Dose-limiting Toxicities [ Time Frame: 4 weeks post-SJCAR19 infusion ]
    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.
  • Complete Response Rate [ Time Frame: 4 weeks post-SJCAR19 infusion ]
    The primary objective for the Phase II study portion is to evaluate the complete response (CR) rates of SJCAR19 in pediatric and young adult patient's ≤ 21 years of age, with relapsed or refractory CD19+ ALL.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03573700 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of CD19-Specific CAR Engineered Autologous T-Cells for Treatment of Relapsed/Refractory CD19+ Acute Lymphoblastic Leukemia
Official Title  ICMJE 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
Brief Summary

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Lymphoblastic Leukemia, in Relapse
  • Acute Lymphoblastic Leukemia, Refractory
Intervention  ICMJE
  • Drug: Cyclophosphamide
    Given IV
    Other Name: Cytoxan
  • Drug: Fludarabine
    Given IV
    Other Name: Fludara
  • Drug: Mesna
    Given IV
    Other Name: Mesnex
  • Device: CliniMACS
    The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest.
  • Biological: CD19- specific CAR engineered autologous T-cells (SJCAR19 product)
    Given IV
Study Arms  ICMJE Experimental: SJCAR19 Therapy

Patients 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.

Interventions:
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
  • Drug: Mesna
  • Device: CliniMACS
  • Biological: CD19- specific CAR engineered autologous T-cells (SJCAR19 product)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 20, 2018)
35
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 1, 2024
Estimated Primary Completion Date July 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Aimee C. Talleur, MD 866-278-5833 referralinfo@stjude.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03573700
Other Study ID Numbers  ICMJE SJCAR19
NCI-2017-01399 ( Registry Identifier: NCI Clinical Trial Registration Proogram )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Pediatric Postmarket Surveillance of a Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party St. Jude Children's Research Hospital
Study Sponsor  ICMJE St. Jude Children's Research Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Aimee C. Talleur, MD St. Jude Children's Research Hospital
PRS Account St. Jude Children's Research Hospital
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP