CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies

Phase 1

Completed

Conditions: B-Cell Lymphoma
Acute Lymphocytic Leukemia
B-Cell Leukemia
B-Non Hodgkin Lymphoma
Lymphoma, Non-Hodgkin
Leukemia, Lymphocytic, B Cell
Acute Lymphoid Leukemia
B-NHL
Acute Lymphoblastic Leukemia
B-All

Interventions: Biological: CD19/CD22 CAR T-Cells
Drug: Fludarabine
Drug: Cyclophosphamide
Procedure: Apheresis
Other: Anti-emetic
Drug: Diphenhydramine
Drug: Acetaminophen
Diagnostic Test: ECG
Diagnostic Test: ECHO
Diagnostic Test: MRI Brain
Procedure: Bone marrow biopsy
Diagnostic Test: Cardiac MRI

Registration Number: NCT03448393

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

B-cell leukemias and lymphomas are cancers that are often difficult to treat. The primary objective of this study is to determine the ability to take a patient's own cells (T lymphocytes) and grow them in the laboratory with the cluster of differentiation 19 (CD19/cluster of differentiation 22-chimeric antigen receptor (CD22-CAR) gene through a process called 'lentiviral transduction (also considered gene therapy) and growing them to large numbers to use as a treatment for hematologic cancers in children and young adults.. Researchers want to see if giving modified CD19/CD22-CAR T cells to people with these cancers can attack cancer cells. In addition, the safety of giving these gene modified cells to humans will be tested at different cell doses. Additional objectives are to determine if this therapy can cause regression of B cell cancers and to measure if the gene modified cells survive in patients' blood.

Objective:

To study the safety and effects of giving CD19/CD22-CAR T cells to children and young adults with B-cell cancer.

Eligibility:

People ages 3-39 with certain cancers that have not been cured by standard therapy. Their cancer tissue must express the CD19 protein.

Design:

A sample of participants blood or bone marrow will be sent to National Institutes of Health (NIH) and tested for leukemia.

Participants will be screened with:

Medical history

Physical exam

Urine and blood tests (including for human immunodeficiency virus (HIV)

Heart and eye tests

Neurologic assessment and symptom checklist.

Scans, bone marrow biopsy, and/or spinal tap

Some participants will have lung tests.

Participants will repeat these tests throughout the study and follow-up.

Participants will have leukapheresis. Blood will be drawn from a plastic tube (intravenous (IV) or needle in one arm then go through a machine that removes lymphocytes. The remaining blood will be returned to the participant's other arm.

Participants will stay in the hospital about 2 weeks. There they will get:

Two chemotherapy drugs by IV

Their changed cells by IV

Standard drugs for side effects

Participants will have frequent follow-up visits for 1 year, then 5 visits for the next 4 years. Then they will answer questions and have blood tests every year for 15 years.

...

Detailed Description: Background:

* Acute lymphoblastic leukemia (ALL) accounts for approximately 25% of childhood cancer. Survival rates have improved, but outcomes for some subgroups, including infants and young adults remain poor, and survival for patients who relapse is \< 50%, despite allogeneic stem cell transplant following second remission.

* Cluster of differentiation 19 (CD19 immune escape has been observed by several groups following CD19-chimeric antigen receptor (CAR) therapy for B-ALL. Investigation of this phenomenon reveals a complex biology responsible for loss or downregulation of CD19 expression observed in these cases.

* Sequential therapy using cluster of differentiation 22 (CD22)-CARs to treat CD19 dim/lo escape is associated with rapid development of resistance due to CD22 downregulation. This trial will test whether simultaneous targeting of CD19 and CD22 using a novel bivalent CD19/22-CAR is safe and feasible.

Objectives:

-Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells that meet established release specifications in children and young adults with CD19+CD22+ B cell ALL, isolated central nervous system (CNS) ALL, or lymphoma following a cyclophosphamide/fludarabine conditioning regimen.

Eligibility:

-Participants between \>= 3 years and \<= 39 years of age, with CD19+/CD22+ B cell ALL, isolated CNS ALL, or lymphoma who have relapsed or have refractory disease after at least one standard chemotherapy regimen and one salvage regimen, with no alternative curative options who meet standard Phase I eligibility criteria.

Design:

* Phase I, 3 + 3 dose escalation design using the following dose levels: -1: 1 x 10\^5 transduced T cells/kg (+/- 20%); 1: 3 x 10\^5 transduced T cells/kg (+/- 20%); 2: 1 x 10\^6 transduced T cells/kg; and 3: 3 x 10\^6 transduced T cells/kg (+/- 20%); 4: 1 x 10\^7 transduced T cells/kg (+/- 20%).

* Participants will receive a lymphodepleting preparative regimen of fludarabine (25 mg/m\^2/day (d) x 3 on Days -4, -3, -2) and cyclophosphamide (900 mg/m\^2/d x 1 on Day -2) followed by infusion of CD19/CD22-CAR T-cells on D0. Participants who are CAR pretreated (with exception for those with an interval hematopoietic stem cell transplantation (HSCT) will receive increased lymphodepleting preparative regimen of fludarabine (30\^mg/m\^2/d x 4 on Days -5, -4, -3, -2) and cyclophosphamide (600 mg/m\^2/d x 2 on Days -3, -2) followed by infusion of CD19/CD22-CAR T-cells on D0. If fludarabine is unavailable, pentostatin may be given as an alternative.

* Patients will be evaluated sequentially for toxicity, antitumor effects, CAR expansion and persistence, as well as research correlatives.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Dose Expansion	Cardiac MRI	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Escalation	CD19/CD22 CAR T-Cells	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	Fludarabine	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	Cyclophosphamide	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	Apheresis	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	Anti-emetic	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	Diphenhydramine	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	Acetaminophen	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	ECG	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	ECHO	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	MRI Brain	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	Bone marrow biopsy	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Escalation	Cardiac MRI	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.
Dose Expansion	CD19/CD22 CAR T-Cells	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	Fludarabine	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	Cyclophosphamide	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	Apheresis	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	Anti-emetic	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	Diphenhydramine	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	Acetaminophen	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	ECG	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	ECHO	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	MRI Brain	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.
Dose Expansion	Bone marrow biopsy	Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at maximum tolerated dose (MTD) or highest dose administered.

Primary Outcome Measures

Name	Time	Method
Grades of Toxicity by Type of Toxicity	From start of lymphodepleting chemotherapy regimen through 30-days after chimeric antigen receptor (CAR) infusion (approximately 5 weeks).	Safety analyses will consist of tabulations of grades of toxicity by type of toxicity assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.
Maximum Tolerated Dose (MTD)	First 28 days after cell infusion	MTD is defined as the dose level immediately below the level at which the enrollment is stopped due to dose-limiting toxicity (DLT). A DLT is defined as an adverse event that is at least possibly related to the cluster of differentiation 19/cluster of differentiation 22 (CD19/CD22)-chimeric antigen receptor (CAR) T cells with onset within the first 28 days after cell infusion.

Secondary Outcome Measures

Name	Time	Method
Number of Participants That Have Successful Manufacture of the Targeted Dose Number of Chimeric Antigen Receptor (CAR) Cells	CAR infusion (Day 0)	Number of participants that have the targeted dose number of CAR cells successfully manufactured (i.e., number of participants enrolled where the correct number of cells are produces at the dose level that are enrolled) as measured by total number of viable cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22) transduced T cells.
Overall Survival	Number of months from CAR cell infusion until date of death or time of censor (max 66.6 months)	Overall survival (OS) will be determined as the time from the date of chimeric antigen receptor (CAR) infusion until death.
Progression-free Survival (PFS)	Number of months from CAR cell infusion until time of disease progression, death, or date of censor (up to 67 months)	PFS is assessed from the date of chimeric antigen receptor (CAR) infusion until the documentation of disease progression or death due to any cause, whichever occurs first. Disease progression was assessed by the Response Criteria Lymphoma and is defined as individual node/lesion must be abnormal with LDI\>1.5 cm and increase by ≥50% from product of perpendicular diameters (PPD) nadir and an increase in longest transverse diameter of a lesion (LDI) or shortest axis perpendicular to LDi (SDI) from nadir 0.5 cm for lesions ≤2 cm, 1.0 cm for lesions \> 2 cm; and the International Working Group and is defined as worse marrow classification with at least a 50% increase in the percentage of marrow blasts.
Clinical Activity (Response) in Children and Young Adults With B-cell Acute Lymphoblastic Leukemia (B-ALL), Isolated Central Nervous System (CNS) ALL, or Lymphoma Who Previously Received Chimeric Antigen Receptor (CAR) Therapy and Those That Are CAR Naive	At Day 28 (+/- 4 days) after CAR cell infusion	Clinical activity (response) in children (age ≥3 years to 17 years) and young adults (age 18 years to ≤ 39 years) was measured by the Response Criteria Lymphoma. Complete Response (CR) is complete metabolic and/or radiographic response. Partial Response (PR) is partial metabolic response or partial remission. Stable Disease (SD) is no metabolic response or 50% decrease from baseline in the sum of products of diameters (SPD) of up to 6 dominant measurable nodes and extra nodal sites. Progressive Disease (PD) is individual node/lesion must be abnormal with longest transverse diameter of a lesion (LDI) \>1.5 cm and increase by ≥50% from product of perpendicular diameters (PPD) nadir and an increase in LDI or shortest axis perpendicular to LDi (SDI) from nadir 0.5 cm for lesions ≤2 cm and/or 1.0 cm for lesions \> 2 cm; also assessed by the International Working Group and PD is defined as worse marrow classification with at least a 50% increase in the percentage of marrow blasts.

Trial Locations

Locations (1): National Institutes of Health Clinical Center
🇺🇸
Bethesda, Maryland, United States
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States