Orphan Indications for CD19 Redirected Autologous T Cells

Phase 2

Recruiting

• Conditions: Infants With Very High Risk KMT2A B-ALL; Pediatric and Young Adult Patientswith Hypodiploid or t(17;19) B-ALL; Patients With Central Nervous System Relapse Who Did Not Receive Cranial Radiation or Bone Marrow Transplantation
• Interventions: Biological: Murine CART19

• Registration Number: NCT04276870
• Lead Sponsor: Stephan Grupp MD PhD

Brief Summary

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-02-14
• Study First Submitted QC: 2020-02-17
• Study First Posted: 2020-02-19
• Study Start: 2020-03-12
• Status Verified: 2025-01
• Last Update Submitted: 2025-04-11
• Last Update Posted: 2025-04-14
• Primary Completion: 2028-03-10
• Study Completion: 2037-03-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 133

Inclusion Criteria

1. Signed informed consent form must be obtained prior to any study procedure.

2. 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

3. Documentation of CD19 tumor expression in bone marrow, peripheral blood, CSF, or tumor tissue.

4. Age 0 to 29 years

5. Adequate organ function defined as:

   1. 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

   2. 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.

6. Adequate performance status defined as Lansky or Karnofsky score ≥ 50

7. Subjects of reproductive potential must agree to use acceptable birth control methods

Exclusion Criteria

1. For subjects with a CNS relapse, prior cranial XRT or BMT for the current relapse is an exclusion.
2. Active hepatitis B or active hepatitis C.
3. HIV Infection.
4. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy.
5. 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.
6. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
7. Pregnant or nursing (lactating) women.
8. Uncontrolled active infection.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Subjects with t(17;19) B-ALL	Murine CART19	-
Subjects with central nervous system (CNS) relapse	Murine CART19	who did not receive cranial radiation (XRT) or bone marrow transplantation (BMT)
Subjects with hypodiploid B-ALL	Murine CART19	-
Infant subjects with very high risk KMT2A B-ALL	Murine CART19	-

Primary Outcome Measures

Name	Time	Method
Event-free survival (EFS)	One year	1 year event-free survival (EFS), where events include no response, relapse, death due to any cause

Secondary Outcome Measures

Name	Time	Method
EFS Rate 1	One year	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
To further evaluate the safety of CART19 in the target patient populations	One year	Frequency and severity of adverse events
EFS rate 2	One year	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
Relapse Free survival 4	One year	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.
MRD conversion	One year	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
Relapse Free survival 2	One year	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
Relapse Free survival 1	One year	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.
Relapse Free survival 3	One year	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

Trial Locations

Locations (1)

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States