Study of huCART19 for Very High-Risk (VHR) Subsets of Pediatric B-ALL

Phase 2 Study of Humanized CD19-directed Chimeric Antigen Receptor-modified T Cells (huCART19) for Very High-Risk Subsets of B Cell Acute Lymphoblastic Leukemia (B-ALL)

This is a phase 2 study to evaluate humanized CD19 redirected autologous T cells (or huCART19 cells) with CD19 expressing relapsed and refractory B-cell acute lymphoblastic leukemia. This study is targeting pediatric and young adult patients aged 3 months - 29 years with CD19+ B cell malignancies in newly diagnosed B-ALL patients predicted to have an exceedingly poor outcome with conventional chemotherapy, in high-risk first relapse, or and in second or greater relapse in this phase 2 trial. In addition, a second cohort will test the efficacy of huCART19 in patients with poor response to prior B cell directed engineered cell therapy.

Inclusion Criteria:

1. Signed informed consent form must be obtained.

2. Relapsed or refractory B-cell ALL:

   a. Cohort A: Patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL who meet one of the following criteria:

   i. Newly diagnosed NCI HR B-ALL with induction failure: M3 marrow (>25% blasts) at end of induction OR

ii. First marrow relapse of B-ALL at < 36 months from diagnosis OR iii. 2nd or greater relapse OR

iv. Any relapse after allogeneic HSCT and ≥ 4 months from SCT at enrollment OR

v. Refractory disease defined as having not achieved an MRD-negative and/or CSF-negative CR after ≥ 2 chemotherapy regimens/cycles of frontline therapy or 1 cycle of reinduction therapy for patients in first relapse OR

vi. Ineligible for allogeneic SCT because of:

1. Comorbid disease
2. Other contraindications to allogeneic SCT conditioning regimen
3. Lack of suitable donor
4. Prior SCT
5. Declines allogeneic SCT as the therapeutic option after documented discussion, with expected outcomes, about the role of SCT with a BMT physician not part of the study team b. Cohort B: Patients previously treated with B cell directed engineered cell therapy who meet one of the following criteria: i. partial response or no response to prior cell therapy ii. CD19+ relapse after prior cell therapy iii. demonstrated early (≤6 months from infusion) B cell recovery suggesting loss of engineered cells c. Patients with prior or current history of CNS3 disease will be eligible if CNS disease is responsive to therapy (at infusion, must meet criteria in Section 5.3 of the protocol)

3. 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.

4. Adequate organ function defined as:

1. A serum creatinine based on age/gender

2. ALT≤ 500 U/L

3. Bilirubin ≤2.0 mg/dl

4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea, < Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the treating investigator

5. Left Ventricular Shortening Fraction (LVSF) ≥ 28% or Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO, or adequate ventricular function documented by a scan or a cardiologist.

   5. Age 3 months to 29 years. 6. Adequate performance status (Lansky or Karnofsky score ≥50). 7. Subjects of reproductive potential must agree to use acceptable birth control methods.

   Exclusion Criteria:

   1. Active hepatitis B or active hepatitis C.
   2. HIV Infection.
   3. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy.
   4. Concurrent use of systemic steroids or immunosuppression 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 or immunosuppression 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.
   5. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
   6. Pregnant or nursing (lactating) women.
   7. Uncontrolled active infection.
   8. Active medical disorder that, in the opinion of the investigator, would substantially increase the risk of uncontrollable CRS or neurotoxicity.