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

NCT03448393 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 18005918-C-0059
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

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. ...

Conditions

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

Keywords

B-Non Hodgkin Lymphoma; Acute Lymphocytic Leukemia; Acute Lymphoblastic Leukemia; B-precursor ALL; B-All; Philadelphia chromosome + ALL; Lymphoma; CD-22 Expressing Tumor; CD-19 expressing tumor; Adoptive Immunotherapy

Outcome Measures

Primary Outcomes (2)

• Grades of Toxicity by Type of Toxicity

  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.

  From start of lymphodepleting chemotherapy regimen through 30-days after chimeric antigen receptor (CAR) infusion (approximately 5 weeks).

• Maximum Tolerated Dose (MTD)

  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.

  First 28 days after cell infusion

Secondary Outcomes (4)

• Number of Participants That Have Successful Manufacture of the Targeted Dose Number of Chimeric Antigen Receptor (CAR) Cells

  CAR infusion (Day 0)

• Overall Survival

  Number of months from CAR cell infusion until date of death or time of censor (max 66.6 months)

• 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)

• 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

Other Outcomes (2)

• Number of Participants With a Dose-limiting Toxicity (DLT)

  First 28 days

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

  Adverse Events were monitored/assessed from the first study intervention, Study Day -4, through day 30 after the study agent (s) was/were administered, an average of 5 weeks.

Study Arms (2)

Dose Escalation

EXPERIMENTAL

Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22)-chimeric antigen receptor (CAR)-transduced T cells at escalating doses.

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

Dose Expansion

EXPERIMENTAL

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.

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

Interventions

CD19/CD22 CAR T-Cells BIOLOGICAL

Cluster of differentiation 19 (CD19)/cluster of differentiation 22 (CD22) chimeric antigen receptor (CAR) T-cells will be infused on Day 0 after lymphodepleting chemotherapy regimen.

Also known as: cluster of differentiation 19 chimeric antigen receptor T-cells, cluster of differentiation 22 chimeric antigen receptor T-cells

Dose Escalation; Dose Expansion

Fludarabine DRUG

Fludarabine is administered as an intravenous (IV) infusion in an appropriate solution over 30 minutes. To prevent undue toxicity the dose will be based on body surface area (BSA) (25-30 mg/m\^2/dose) on Days -4, -3, -2 or Days -5, -4, -3, -2.

Also known as: Fludara

Dose Escalation; Dose Expansion

Cyclophosphamide DRUG

Cyclophosphamide will be diluted in an appropriate solution and infused over one hour. The dose will be based on the body surface area (BSA), at 900 mg/m\^2/dose after fludarabine infusion on Day -2 or 600 mg/m\^2/dose on Days -3 \& -2.

Also known as: Cytoxan

Dose Escalation; Dose Expansion

Apheresis PROCEDURE

According to institutional standards.

Dose Escalation; Dose Expansion

Anti-emetic OTHER

Prophylaxis and treatment.

Dose Escalation; Dose Expansion

Diphenhydramine DRUG

Pre-medication: 0.5-1 mg/kg/dose (maximum 50 mg/dose) by mouth or intravenous over 10-15 minutes.

Also known as: Benadryl, Banophen, Nytol

Dose Escalation; Dose Expansion

Acetaminophen DRUG

Pre-medication: 15 mg/kg/dose (maximum 650 mg/dose by mouth).

Also known as: Tylenol, ofirmev, FeverAll

Dose Escalation; Dose Expansion

ECG DIAGNOSTIC_TEST

Pre-cell infusion.

Also known as: Electrocardiogram

Dose Escalation; Dose Expansion

ECHO DIAGNOSTIC_TEST

Pre-cell infusion.

Also known as: Echocardiogram

Dose Escalation; Dose Expansion

MRI Brain DIAGNOSTIC_TEST

Pre-cell infusion.

Also known as: Magnetic resonance imaging

Dose Escalation; Dose Expansion

Bone marrow biopsy PROCEDURE

Pre-cell infusion.

Also known as: BM biopsy

Dose Escalation; Dose Expansion

Cardiac MRI DIAGNOSTIC_TEST

Screening

Also known as: Cardiac magnetic resonance imaging

Dose Escalation; Dose Expansion

Eligibility Criteria

• Age: 3 Years - 39 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may not qualify if:

• Diagnosis
• Participant must have a B cell acute lymphoblastic leukemia (ALL) (inclusive of chronic myeloid leukemia (CML) with ALL transformation) or lymphoma and must have relapsed or refractory disease after at least one standard chemotherapy regimen and one salvage regimen. In view of the principal investigator (PI) and the primary oncologist, there must be no available alternative curative therapies and subjects must be either ineligible for allogeneic stem cell transplant (SCT), have refused SCT, recurred after SCT, or have disease activity that prohibits SCT at the time of enrollment. Participants who have undergone autologous SCT will be eligible, and participants that have undergone allogeneic SCT will be eligible if, in addition to meeting other eligibility criteria, they have no evidence of graft versus host disease (GVHD) and have been without immunosuppressive agents for at least 30 days. Participants with Philadelphia chromosome + ALL must have failed prior tyrosine kinase inhibitor.
• Participants must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis. For those being considered for reinfusions, measurable or evaluable disease is not required at the time of reinfusion.
• CD22/CD19 expression
• CD19 expression must be detected on greater than 15% of the malignant cells by immunohistochemistry or greater than 90% by flow cytometry. The choice of whether to use flow cytometry or immunohistochemistry will be determined by what is the most easily available tissue sample in each participant. In general, immunohistochemistry will be used for lymph node biopsies, flow cytometry will be used for peripheral blood and bone marrow samples. CD22+ B cell malignancy is required and CD22 expression levels will be documented when available, but a specific level of expression is not an eligibility requirement; it may be documented as positive or negative.
• Age:
• Greater than or equal to 3 years of age (and at least 15 kg) and less than or equal to 39 years of age at time of enrollment (greater than or equal to 3 years to less than or equal to 39 years). NOTE: The first participant in each dose cohort must be greater than or equal to 18 years of age.
• Clinical Performance
• Clinical performance status: Participants greater than or equal to 16 years of age: Karnofsky greater than or equal to 50%; Participants \< 16 years of age: Lansky scale greater than or equal to 50%. Subjects who are unable to walk because of paralysis, but who are upright in a wheelchair will be considered ambulatory for the purpose of calculating the performance score.
• Participants must have adequate organ and marrow function as defined below:
• leukocytes greater than or equal to 750/mcL\*
• platelets greater than or equal to 50,000/mcL\*
• total bilirubin less than or equal to 2 X upper limit of normal (ULN) (except in the case of subjects with documented Gilbert's disease \> 3x ULN)
• Aspartate aminotransferase (AST)serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)serum glutamate pyruvate transaminase (SGPT) less than or equal to 10 X institutional upper limit of normal
• creatinine less than or equal to the maximum for age listed in the table below

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Silbert SK, Madan S, Holland EM, Steinberg SM, Little L, Foley T, Epstein M, Sarkisian A, Lee DW, Nikitina E, Kakumanu S, Ruppin E, Shalabi H, Yates B, Shah NN. A comprehensive analysis of adverse events in the first 30 days of phase 1 pediatric CAR T-cell trials. Blood Adv. 2023 Sep 26;7(18):5566-5578. doi: 10.1182/bloodadvances.2023009789.

  PMID: 37486616 DERIVED

• Shalabi H, Qin H, Su A, Yates B, Wolters PL, Steinberg SM, Ligon JA, Silbert S, DeDe K, Benzaoui M, Goldberg S, Achar S, Schneider D, Shahani SA, Little L, Foley T, Molina JC, Panch S, Mackall CL, Lee DW, Chien CD, Pouzolles M, Ahlman M, Yuan CM, Wang HW, Wang Y, Inglefield J, Toledo-Tamula MA, Martin S, Highfill SL, Altan-Bonnet G, Stroncek D, Fry TJ, Taylor N, Shah NN. CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR. Blood. 2022 Aug 4;140(5):451-463. doi: 10.1182/blood.2022015795.

  PMID: 35605184 DERIVED

• Singh N. Modified T cells as therapeutic agents. Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):296-302. doi: 10.1182/hematology.2021000262.

  PMID: 34889384 DERIVED

• Molina JC, Steinberg SM, Yates B, Lee DW, Little L, Mackall CL, Shalabi H, Shah NN. Factors Impacting Overall and Event-Free Survival following Post-Chimeric Antigen Receptor T Cell Consolidative Hematopoietic Stem Cell Transplantation. Transplant Cell Ther. 2022 Jan;28(1):31.e1-31.e9. doi: 10.1016/j.jtct.2021.10.011. Epub 2021 Oct 20.

  PMID: 34687939 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Leukemia, B-Cell; Lymphoma, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Burkitt Lymphoma; Philadelphia Chromosome; Lymphoma

Interventions

fludarabine; fludarabine phosphate; Cyclophosphamide; Blood Component Removal; Antiemetics; Diphenhydramine; Acetaminophen; Electrocardiography; Echocardiography; Magnetic Resonance Imaging

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Epstein-Barr Virus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Translocation, Genetic; Chromosome Aberrations; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Therapeutics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Central Nervous System Agents; Therapeutic Uses; Gastrointestinal Agents; Ethylamines; Amines; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Acetanilides; Anilides; Amides; Aniline Compounds; Heart Function Tests; Diagnostic Techniques, Cardiovascular; Diagnostic Techniques and Procedures; Diagnosis; Electrodiagnosis; Cardiac Imaging Techniques; Diagnostic Imaging; Ultrasonography; Tomography

Results Point of Contact

• Title: Dr. Nirali N. Shah
• Organization: National Cancer Institute

shahnn@mail.nih.gov

240-760-6970

Study Officials

• Nirali N Shah, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 27, 2018
• First Posted: February 28, 2018
• Study Start: March 26, 2018
• Primary Completion: July 10, 2024
• Study Completion: January 13, 2025
• Last Updated: June 4, 2025
• Results First Posted: June 4, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

Locations

US (1)