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Modified Immune Cells (huCART19) in Treating Pediatric Patients with Relapsed or Refractory Very High-Risk B Acute Lymphoblastic Leukemia

Trial Status: Active

This phase II trial studies how well modified immune cells (huCART19) work in treating pediatric patients with very high-risk B cell acute lymphoblastic leukemia that has come back or does not respond to treatment. huCART19 are genetically modified white blood cells (T cells) that recognize tumor cells and normal antibody-producing cells called B cells, but not other normal cells in the body. huCART19 may help to identify and kill the tumor cells.

Inclusion Criteria

  • Signed informed consent form must be obtained.
  • Relapsed or refractory B-cell ALL.
  • Cohort A: Patients with newly diagnosed very high risk (VHR) B-ALL or high-risk relapse of B-ALL who meet one of the following criteria: * Newly diagnosed National Cancer Institute (NCI) high risk (HR) B-ALL with induction failure: M3 marrow (> 25% blasts) at end of induction OR * First marrow relapse of B-ALL at < 36 months from diagnosis OR * 2nd or greater relapse OR * Any relapse after allogeneic hematopoietic stem cell transplantation (HSCT) and >= 4 months from stem cell transplantation (SCT) at enrollment OR * Refractory disease defined as having not achieved an minimal residual disease (MRD)-negative and/or cerebrospinal fluid (CSF)-negative complete remission (CR) after >= 2 chemotherapy regimens/cycles of front line therapy or 1 cycle of reinduction therapy for patients in first relapse OR * Ineligible for allogeneic SCT because of: ** Comorbid disease. ** Other contraindications to allogeneic SCT conditioning regimen. ** Lack of suitable donor. ** Prior SCT. ** Declines allogeneic SCT as the therapeutic option after documented discussion, with expected outcomes, about the role of SCT with a bone marrow transplant (BMT) physician not part of the study team.
  • Cohort B: Patients previously treated with B cell directed engineered cell therapy who meet one of the following criteria: * Partial response or no response to prior cell therapy. * CD19+ relapse after prior cell therapy. * Demonstrated early (=< 6 months from infusion) B cell recovery suggesting loss of engineered cells.
  • Patients with prior or current history of central nervous system (CNS)3 disease will be eligible if CNS disease is responsive to therapy.
  • Documentation of CD19 tumor expression in bone marrow, peripheral blood, CSF, or tumor tissue by flow cytometry at relapse (or a recent sample in the case of refractory disease). If the patient has received CD19-directed therapy, then the flow cytometry should be obtained after this therapy to show CD19 expression.
  • Maximum serum creatinine (SCr) based on age/gender as follows: * 1 to < 2 years: 0.6 mg/dL (male and female) * 2 to < 6 years: 0.8 mg/dL (male and female) * 6 to < 10 years: 1.0 mg/dL (male and female) * 10 to < 13 years: 1.2 mg/dL (male and female) * 13 to < 16 years: 1.5 mg/dL (male); 1.5 mg/dL (female) * >= 16 years: 1.7 mg/dL (male); 1.4 mg/dL (female)
  • Alanine aminotransferase (ALT) =< 500 U/L.
  • Bilirubin =< 2.0 mg/dL
  • Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea, < grade 3 hypoxia; diffusion capacity of the lung for carbon monoxide (DLCO) >= 40% (corrected for anemia) if pulmonary function tests (PFTs) are clinically appropriate as determined by the treating investigator.
  • Left ventricular shortening fraction (LVSF) >= 28% or ejection fraction (LVEF) >= 45% confirmed by echocardiogram (ECHO), or adequate ventricular function documented by a scan or a cardiologist.
  • Adequate performance status (Lansky or Karnofsky score >= 50).
  • Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria

  • Active hepatitis B or active hepatitis C.
  • Human immunodeficiency virus (HIV) infection.
  • Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy.
  • Concurrent use of systemic steroids at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of physiologic replacement hydrocortisone or inhaled steroids is permitted as well.
  • CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
  • Pregnant or nursing (lactating) women.
  • Uncontrolled active infection.

Pennsylvania

Philadelphia
Children's Hospital of Philadelphia
Status: ACTIVE
Contact: Shannon L. Maude
Phone: 215-590-5476

PRIMARY OBJECTIVES:

I. To determine efficacy of autologous anti-CD19 chimeric antigen receptor (CAR) T-cell receptor (TCR)-zeta/4-1BB-transduced T-lymphocytes huCART19 (huCART19).

SECONDARY OBJECTIVES:

I. To describe additional efficacy endpoints.

II. To further evaluate the safety of huCART19 in pediatric acute lymphoblastic leukemia (ALL).

EXPLORATORY OBJECTIVES:

I. Characterize the pharmacokinetic (PK) profile of huCART19.

II. Evaluate bioactivity of huCART19 cells.

III. Describe checkpoint pathways and markers of T cell exhaustion.

OUTLINE:

Patients undergo apheresis at week -4 to -3. Beginning 2-5 days after completion of lymphodepleting chemotherapy, patients receive autologous anti-CD19 CAR TCR-zeta/4-1BB-transduced T-lymphocytes huCART19 intravenously (IV) on day 0.

After completion of study treatment, patients are followed up at 28 days, monthly for months 2-6, then at 9 and 12 months, and optionally for up to 15 years (long-term follow up).

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Children's Hospital of Philadelphia

Principal Investigator
Shannon L. Maude

  • Primary ID 18CT014
  • Secondary IDs NCI-2019-02388, 18-015566
  • Clinicaltrials.gov ID NCT03792633