Orphan Indications for CD19 Redirected Autologous T Cells

Study Overview
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Brief Summary
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This is an open-label, four-cohort, phase 2 study to determine the efficacy of CART19 in pediatric and young adult patientswith hypodiploid (Cohort A) or t(17;19) B-ALL (Cohort B), infants with very high risk KMT2A B-ALL (Cohort C), and in patients with central nervous system (CNS) relapse who did not receive cranial radiation (XRT) or bone marrow transplantation (BMT) (Cohort D).

Official Title
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CD19-Directed Chimeric Antigen Receptor CD19 Redirected Autologous T Cells (CART19) for Orphan Indications of Pediatric B Cell Acute Lymphoblastic Leukemia (B ALL)

Conditions
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Pediatric and Young Adult Patientswith Hypodiploid or t(17;19) B-ALL, Infants With Very High Risk KMT2A B-ALL, Patients With Central Nervous System Relapse Who Did Not Receive Cranial Radiation or Bone Marrow Transplantation

Intervention / Treatment
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* Biological: Murine CART19


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form must be obtained prior to any study procedure. Male and female patients with documented CD19+ B-ALL a.Cohort A & B: Patients, regardless their response to initial or relapsed B ALL therapy, with the following characteristics: i.Cohort A: Subjects with confirmation of a hypodiploid karyotype (chromosome number fewer than 45) ii.Cohort B: Subjects with cytogenetic confirmation of the chromosomal translocation t(17;19) (Cohort B) b.Cohort C: Infants w/ newly diagnosed KMT2A rearranged B-ALL classified as very high risk by the following criteria: i.Age < 3 months at diagnosis ii.Age < 6 months and WBC > 300,000x109/L at diagnosis or a poor prednisone response in induction iii.MRD positive > 0.01 (or PCR > 104) after 2 courses of standard infant ALL therapy. c.Cohort D: Subjects in a first or greater CNS relapse, prior to therapy with cranial XRT or HSCT for the current relapse Expression of CD19 on leukemic blasts demonstrated by flow cytometry of bone marrow, cerebrospinal fluid, or peripheral blood Age 0 to 29 years Adequate organ function defined as: A serum creatinine based on age/gender as follows: Maximum Serum Creatinine (mg/dL) Age Male Female 0 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1.0 1.0 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4 ≥ 16 years 1.7 1.4 Adequate liver function: i.ALT≤ 5 x ULN; ALT ii.Total bilirubin ≤ 3 x ULN iii.ALT and/or bilirubin results that exceed this range are acceptable if, in the opinion of the physician-investigator (or as confirmed by liver biopsy), the abnormalities are directly related to ALL infiltration of the liver. c.Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and < Grade 3 hypoxia; DLCO ≥ 40% (corrected for anemia) if PFTs are clinically appropriate as determined by the physician-investigator. d.Left Ventricular Shortening Fraction (LVSF) ≥ 28%, or Left Ventricular Ejection Fraction (LVEF) ≥ 45% by echocardiogram. In cases where quanitative assessment of LVSF/LVEF is not possible, a statement by the cardiologist that the ECHO shows qualititatively normal ventricular function wll suffice. Adequate performance status defined as Lansky or Karnofsky score ≥ 50 Subjects of reproductive potential must agree to use acceptable birth control methods Exclusion Criteria: For subjects with a CNS relapse, prior cranial XRT or BMT for the current relapse is an exclusion. Active hepatitis B or active hepatitis C. 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.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 29 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subjects with hypodiploid B-ALL<br> | Biological: Murine CART19<br>* CART19 cells transduced with a lentiviral vector to express anti-CD19 scFv:41-BB:TCRζ, administered by IV injection with a planned dose of 5x106 CART19 cells/kg on day 0 with possible reinfusion/retreatment<br>|
| Experimental: Subjects with t(17;19) B-ALL<br> | Biological: Murine CART19<br>* CART19 cells transduced with a lentiviral vector to express anti-CD19 scFv:41-BB:TCRζ, administered by IV injection with a planned dose of 5x106 CART19 cells/kg on day 0 with possible reinfusion/retreatment<br>|
| Experimental: Infant subjects with very high risk KMT2A B-ALL<br> | Biological: Murine CART19<br>* CART19 cells transduced with a lentiviral vector to express anti-CD19 scFv:41-BB:TCRζ, administered by IV injection with a planned dose of 5x106 CART19 cells/kg on day 0 with possible reinfusion/retreatment<br>|
| Experimental: Subjects with central nervous system (CNS) relapse<br>who did not receive cranial radiation (XRT) or bone marrow transplantation (BMT) | Biological: Murine CART19<br>* CART19 cells transduced with a lentiviral vector to express anti-CD19 scFv:41-BB:TCRζ, administered by IV injection with a planned dose of 5x106 CART19 cells/kg on day 0 with possible reinfusion/retreatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | 1 year event-free survival (EFS), where events include no response, relapse, death due to any cause | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFS Rate 1 | Modified EFS rate in CNS relapse patients, using a definition of events that includes no response, relapse, death, need for XRT or need for BMT | One year | 
| To further evaluate the safety of CART19 in the target patient populations | Frequency and severity of adverse events | One year | 
| EFS rate 2 | Modified EFS rate in patients with early CNS relapsed B-ALL (CR1 <18 months) and those with late CNS relapsed B-ALL (CR1 >18 months) using a definition of events that includes no response, relapse, death, need for XRT or need for BMT | One year | 
| MRD conversion | Rate of MRD conversion to less than 0.01% (in patients with MRD) 28 days after CART19 therapy in patients with t(17;19) B-ALL, hypodiploid B-ALL, and very high risk infant B-ALL | One year | 
| Relapse Free survival 1 | Relapse-free survival (RFS) at one year in patients with hypodiploid B-ALL, patients with t(17;19) B-ALL, and very high risk infant B-ALL regardless of their initial response to B-ALL therapy and in patients with CNS relapse who did not receive cranial XRT or BMT after CART19 and who achieved a complete remission following CART19 therapy. | One year | 
| Relapse Free survival 2 | RFS at one year in patients with hypodiploid B-ALL who were MRD negative at end of induction and those who were MRD positive at end of induction during upfront therapy | One year | 
| Relapse Free survival 3 | RFS at one year in patients with t(17;19) B-ALL who were MRD negative at end of induction and those who were MRD positive at end of induction during upfront therapy | One year | 
| Relapse Free survival 4 | RFS at one year in very high risk infants with KMT2A rearrangement who were MRD negative at end of induction and those who were MRD positive at end of induction. | One year |