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

Acute Lymphoid Leukemia Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03792633
• Other study ID #: 831916
• Secondary ID: 18CT014
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 18, 2019
• Est. completion date: August 2024

Study information

• Verified date: August 2023
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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 1-29 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 100
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 29 Years

Eligibility

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) 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 4

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.

Related Conditions & MeSH terms

• Acute Lymphoid Leukemia
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Biological:
• huCART19
huCART19 infusion

Locations

Country	Name	City	State
United States	Children's Hospital of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pennsylvania	Children's Hospital of Philadelphia

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	1-year Event-Free Survival in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL		1 year
Primary	1-year Event-Free Survival in patients with poor response to prior B cell directed engineered cell therapy		1 year
Secondary	Overall Remission Rate (Cohort A)	Overall remission rate as determined by the response at day 28, computed as the proportion of subjects with CR or Cri, in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL.	28 Days
Secondary	Overall Remission Rate (Cohort B)	Overall remission rate as determined by the response at day 28, computed as the proportion of subjects with CR or Cri, in patients with poor response to prior B cell directed engineered cell therapy.	28 Days
Secondary	2-year Event-Free Survival in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL (cohort A).		2 years
Secondary	2-year Event-Free Survival in patients with poor response to prior B cell directed engineered cell therapy (cohort B)		2 years
Secondary	2-year Relapse-Free Survival in patients with newly diagnosed VHR B-ALL or high-risk relapse of B-ALL (cohort A).		2 years
Secondary	2-year Relapse-Free Survival in patients with poor response to prior B cell directed engineered cell therapy (cohort B)		2 years
Secondary	Frequency and severity of adverse events		2 years