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CAR-20/19-T Cells in Pediatric and Young Adult Patients With Relapsed/Refractory B Cell ALL (CAR-20/19-T)

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ClinicalTrials.gov Identifier: NCT04049383
Recruitment Status : Recruiting
First Posted : August 8, 2019
Last Update Posted : October 25, 2021
Sponsor:
Collaborator:
Children's Hospital and Health System Foundation, Wisconsin
Information provided by (Responsible Party):
Julie-An M. Talano, Medical College of Wisconsin

Tracking Information
First Submitted Date  ICMJE August 6, 2019
First Posted Date  ICMJE August 8, 2019
Last Update Posted Date October 25, 2021
Actual Study Start Date  ICMJE October 16, 2020
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 6, 2019)
  • Determine the safety (dose level) of CAR-20/19-T cell administration in relapsed refractory B-ALL. [ Time Frame: 40 months ]
    Safety will be determined by assessments of CRS using the Lee et al. grading scale [1] and adverse events via NCI CTCAE version 5.0. Response assessment occur initially at Day +28 post-treatment (+/- 3 days) with CAR-20/19-T cells. Ongoing response assessment will continue until progression and/or death up to 2 years (see Table 1), after which patients will be transitioned to a long-term follow-up protocol.
  • Determine the feasibility to manufacture CAR-20/19-T cells locally from pediatric and young adult apheresis products using the CliniMACS Prodigy Cell processing device. [ Time Frame: 40 months ]
    Feasibility of CAR-20/19-T cell production by the CliniMACS Prodigy processing device (Miltenyi Biotec) will be measured. At minimum, we expect to reach our target CAR-20/19-T cell dose in at least 75% of subjects with an adequate T cell starting dose. Feasibility will be measured at the end of the study after completion of accrual. If >25% of subjects with an adequate T cell starting dose were unable to achieve goal CAR-20/19-T cell dose, we would deem that this technique is not a feasible method for production.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2019)
  • Determine the anti-tumor responses as measured by response rates. [ Time Frame: 40 months ]
  • Describe the duration of response for responding patients. [ Time Frame: 40 months ]
  • Determine persistence of CAR-20/19-T cells. [ Time Frame: 40 months ]
  • Determine the effects of CAR-20/19-T infusion on non-neoplastic CD19 & CD20 B cells in vivo. [ Time Frame: 40 months ]
  • Evaluate MRD using molecular technologies. [ Time Frame: 40 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE CAR-20/19-T Cells in Pediatric and Young Adult Patients With Relapsed/Refractory B Cell ALL
Official Title  ICMJE Phase 1 Study of Autologous T Cells Engineered to Contain an Anti-CD19 and Anti-CD20 scFv Coupled to CD3ζ and 4-1BB Signaling Domains in Pediatric and Young Adult Patients With Relapsed/ Refractory CD19 or CD20 B-cell Acute Lymphoblastic Leukemia
Brief Summary This is a phase 1, interventional, open label, treatment study designed to evaluate the safety and feasibility of infusion of CAR-20/19-T in pediatric and young adult subjects with B cell ALL that have relapsed after prior therapies or refractory disease and are not candidates for curative intent standard therapy. There will be two phases of this study. A dose escalation phase to determine the safe CAR-20/19-T cell dose in patients B-cell ALL. Once the desired dose has been identified there will be a 6-patient dose expansion phase at the specified dose level.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
There will be two phases of this study. A dose escalation phase to determine the safe CAR-20/19-T cell dose in patients B-cell ALL. Once the desired dose has been identified there will be a 6-patient dose expansion phase at the specified dose level.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Lymphoblastic Leukemia, in Relapse
  • Acute Lymphoblastic Leukemia With Failed Remission
  • Acute Lymphoblastic Leukemia Recurrent
  • Acute Lymphoblastic Leukemia Not Having Achieved Remission
  • Acute Lymphoblastic Leukemia, Pediatric
  • Acute Lymphoblastic Leukemia
Intervention  ICMJE Biological: CAR-20/19-T cells

The investigational agent in this protocol is the CAR-20/19-T cells.CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Patients will receive one of four dose levels of CAR-20/19-T cells based on our dose escalation design (Section 6). Cell dose will be maxed at 80 kg.

Dose Level -1: 1 x 10*5 CAR-20/19-T cells/kg Dose Level 0: 2.5 x10*5 CAR-20/19-T cells/kg (starting dose level) Dose Level 1: 7.5 x10*5 CAR-20/19-T cells/kg Dose Level 2: 2.5 x10*6 CAR-20/19-T cells/kg (goal cell dose)

Study Arms  ICMJE
  • Experimental: Dose Escalation Phase
    Intervention: Biological: CAR-20/19-T cells
  • Experimental: Dose Expansion Phase
    Intervention: Biological: CAR-20/19-T cells
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: August 6, 2019)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2023
Estimated Primary Completion Date October 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Diagnosis of B-cell ALL: Patients must be aged ≥ 1 years and ≤ 39.99 years with relapsed or refractory disease and no available curative options that meet clinical criteria to initiate treatment.
  2. Relapsed or refractory B cell ALL defined as one of the following:

    1. Primary refractory disease
    2. Relapsed or refractory disease after 2 or more lines of systemic therapy
    3. Relapsed or refractory disease after allogeneic transplant provided subject is at least 100 days from stem cell transplant at the time of enrollment and off of immunosuppressive medications for at least 4 weeks prior to enrollment
  3. Morphological disease in the bone marrow (> 5% blasts).
  4. Patients with B-cell ALL must have either CD19 or CD20 positive disease on their most recent bone marrow performed. A minimum of 5% CD19 and/or CD20 positivity on prior or bone marrow aspirate (BMA) or biopsy is required.
  5. Subjects with Ph+ ALL are eligible if they have relapsed or have refractory disease and have failed two tyrosine kinase inhibitors.
  6. Absolute CD3+ T cell count ≥100/mm3.

    a. Subjects who receive chemotherapy and/or steroids after CD3+ T-cell count, but before apheresis, will require this test to be repeated.

  7. Lumbar puncture with CSF analysis by cytology with no evidence of disease.
  8. Karnofsky/Lansky performance score ≥70. See Appendix A for scales.
  9. Normal Baseline Neurological Evaluation: Mini-Mental Status Exam Score 24-30 for > 16 yo (Appendix B).
  10. Adequate hepatic function, defined as AST and ALT <3 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase <2 x ULN, or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease.
  11. Adequate renal function defined as creatinine clearance or radioisotope GFR > 70 ml/min/1.73 M2
  12. Able to give informed consent if > 18 years, or with a legal guardian capable of giving informed consent if < 18 years.
  13. Agree to practice birth control during the study.
  14. Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an ECHO.
  15. No clinically significant arrhythmias.
  16. Adequate pulmonary function as indicated by room air oxygen saturation of ≥ 92% and no clinically significant pleural effusion.
  17. Expected survival >12 weeks.
  18. Negative urine or serum pregnancy test in females of child bearing potential at study entry and again within 48 hours' prior lymphodepleting chemotherapy.
  19. Patients with prior CD19 or CD20 therapy (e.g., blinatumomab, CART19, rituximab) treatment require repeat BMA/biopsy post-CD19 or CD20 therapy treatment that demonstrates CD19 or CD20 positive disease.
  20. Meet criteria regarding fertility and contraception detailed in section 4.4.
  21. Central line access will be required for CAR-20/19-T cell infusion.

Exclusion Criteria:

  1. Positive beta-HCG in female of child-bearing potential defined as per table 1.
  2. Patients with known systemic allergy to bovine or murine products.
  3. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection. A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing.
  4. History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon: such as systemic lupus erythematous, Wegner's glomerulonephritis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (AIHA, ITP) requiring steroid therapy defined as >20 mg of prednisone.
  5. Presence of ≥ grade 3 non-hematologic toxicities as per CTCAE version 5 from any previous treatment unless it is felt to be due to underlying disease.
  6. Concurrent use of investigational therapeutic agents or enrollment on another therapeutic clinical trial at any institution.
  7. Refusal to participate in the long-term follow-up protocol.
  8. CNS Abnormalities

    1. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was >4 weeks before enrollment and a remission documented within 4 weeks of planned CAR-T cell infusion. Patients will be excluded if they have any signs of neurotoxicity at baseline or evidence of chloroma or leukemic infiltrates on MRI.
    2. Presence of CNS-3 disease defined as detectable cerebrospinal blast cells in a sample of CSF with ≥ 5 WBCs per mm3 with or without neurological changes, and presence of CNS-2 disease defined as detectable cerebrospinal blast cells in a sample of CSF with < 5 WBCs per mm3 with neurological changes Note: Subjects with CNS-1 (no detectable leukemia in the CSF) and those with CNS-2 without clinically evident neurological changes are eligible to participate in the study.
    3. History or presence of any CNS disorder, such as a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, any autoimmune disease with CNS involvement, posterior reversible encephalopathy syndrome (PRES), or cerebral edema
  9. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are <100 days' post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
  10. Anti-CD20 antibody treatment within 4 weeks of cell infusion.
  11. Anti-CD19 antibody treatment within 4 weeks of cell infusion
  12. Cytotoxic chemotherapy other than lymphodepletion within 14 days of CAR-T cell infusion.
  13. Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than replacement dose steroids) within 7 days prior to apheresis collection for CAR-T cells. TKIs must be held for 5 half lives or 7 days whichever is shorter prior to enrollment.
  14. Patients post solid organ transplant who develop high grade lymphomas or leukemias.
  15. Concurrent active malignancy (exceptions: treated solid malignancy in >5 years' remission, treated basal or squamous cell carcinomas of the skin).
  16. History of concomitant genetic syndrome associated with bone marrow failure such as Fanconi anemia, Kostmann syndrome, or Shwachman-Diamond syndrome
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year to 39 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Meredith Beversdorf, RN 414-266-5891 mbeversdorf@chw.org
Contact: Emily Ruszkiewicz, BS 414-266-4092 eruszkiewicz@mcw.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04049383
Other Study ID Numbers  ICMJE CAR-20/19-T
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Julie-An M. Talano, Medical College of Wisconsin
Study Sponsor  ICMJE Medical College of Wisconsin
Collaborators  ICMJE Children's Hospital and Health System Foundation, Wisconsin
Investigators  ICMJE
Principal Investigator: Julie-An Talano, MD Medical College of Wisconsin
PRS Account Medical College of Wisconsin
Verification Date October 2021

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