Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma

NCT03696784 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: LCCC 1813-ATLK12CA120780
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

This research study combines 2 different ways of fighting disease: antibodies and T cells. Both antibodies and T cells have been used to treat patients with cancers, and both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to create a more effective treatment. The treatment being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. Prior studies have shown that a new gene can be put into T cells and will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells because they have a substance on the outside of the cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells seem to kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown. Preliminary results have shown that subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome and neurotoxicity. In this study, to help reduce cytokine release syndrome and/or neurotoxicity symptoms, the ATLCAR.CD19 cells have a safety switch that, when active, can cause the cells to become dormant. These modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the subject experiences moderate to severe cytokine release syndrome and or neurotoxicity as a result of being given iC9-CAR19 cells, the subject can be given a dose of a second study drug, AP1903, if standard interventions fail to alleviate the symptoms of cytokine release syndrome and/or neurotoxicity. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The ultimate goal is to determine what dose of AP1903 can be given that reduces the severity of the cytokine release syndrome and/or neurotoxicity, but still allows the remaining iC9-CAR19 cells to effectively fight the lymphoma. The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable in patients with relapsed/refractory B-cell lymphoma, primary central nervous system lymphoma and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Conditions

Lymphoma; Lymphoma, B-Cell; Immune System Diseases; Immunoproliferative Disorders; Lymphatic Diseases

Keywords

CAR T cells; CD19; Lymphoma; AP1903; Cytokine Release Syndrome; Neurotoxicity; Rimiducid

Outcome Measures

Primary Outcomes (1)

• Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells

  Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. ICANS symptoms will be graded per ASBMT ICANS Consensus Grading for Adults (scale from 1-mild to 4-critical) and cytokine release syndrome (CRS) symptoms will be graded according to ASBMT CRS Consensus Grading (a scale from 1-mild to 5-death).

  4 weeks

Secondary Outcomes (9)

• Identify a recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in subjects with relapsed or refractory B-cell lymphoma or CLL/SLL

  4 weeks

• Survival of iC9-CAR19 T cells in vivo

  15 years

• Overall response rate (ORR) (rate of Complete Response (CR)) mediated by autologous iC9-CAR19 T cells administered to subjects with relapsed or refractory B-cell lymphoma or CLL/SLL

  15 years

• Overall survival (OS) in subjects with relapsed or refractory B-cell lymphoma or CLL/SLL following infusion of iC9-CAR19 T cells

  15 years

• Progression free survival (PFS) in subjects with relapsed or refractory B-cell lymphoma or CLL/SLL following infusion of iC9-CAR19 T cells

  15 years

Study Arms (2)

Single Arm iC9.CAR19 T cells

EXPERIMENTAL

The safety of iC9-CAR19 cells will be investigated using the 3+3 design. Dose level (DL) Dose (#transduced cells/kg) -1 1 x 10\^5 1. 1 x 10\^6 2. 2 x 10\^6 DL1 will enroll 3 subjects. If no toxicity within 4 weeks, then DL 2 will enroll 3 subjects. If toxicity in 1/3 subjects in DL 1, 3 more subjects will be enrolled. If DL 1 is not tolerable, a de-escalation to DL -1 will enroll 3 subjects. If 3 subjects at the higher dose do not have DLTs more will be enrolled at that dose to get more information about toxicity. Lymphodepleting chemotherapy of IV bendamustine 70 mg/m2 and IV fludarabine 30 mg/m2/day for 3 consecutive days will be given within 2-14 days prior to cell infusion. AP1903 (0.4 mg/kg), a dimerizing agent to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T cell death by apoptosis will be given to subjects who develop severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS).

Biological: iC9-CAR19 T cells; Drug: Bendamustine; Drug: Fludarabine; Drug: AP1903; Drug: Cyclophosphamide

Expansion Cohort iC9-CAR19 cells

EXPERIMENTAL

After the tolerable cell dose (TCD) has been determined in adults, up to 18 additional subjects may be enrolled in an expansion cohort at the TCD. A TCD is defined as the dose at which approximately 0.20 of subjects experience dose limiting toxicity (0 - 1 out of 6 subjects).

Biological: iC9-CAR19 T cells; Drug: Bendamustine; Drug: Fludarabine; Drug: AP1903; Drug: Cyclophosphamide

Interventions

iC9-CAR19 T cells BIOLOGICAL

iC9-CAR19 T cells will be given by a licensed healthcare provider via intravenous injection over 5-10 minutes through either a peripheral or a central line.

Expansion Cohort iC9-CAR19 cells; Single Arm iC9.CAR19 T cells

Bendamustine DRUG

70mg/m2 IV given as a daily infusion for 3 days per institutional guidelines 2 - 14 days prior to the T cell infusion.

Also known as: Treanda, Bendeka

Expansion Cohort iC9-CAR19 cells; Single Arm iC9.CAR19 T cells

Fludarabine DRUG

30 mg/m2 given as a daily infusion for 3 days per institutional guidelines 2 - 14 days prior to the T cell infusion

Also known as: Fludara

Expansion Cohort iC9-CAR19 cells; Single Arm iC9.CAR19 T cells

AP1903 DRUG

0.4 mg/kg of AP1903 as an IV infusion over 2 hrs for subjects who develop Grade 4 cytokine release syndrome (CRS) or grade ≥3 CRS that is unresponsive to standard of care interventions , subjects who develop grade ≥3 Immune effector cell-associated neurotoxicity syndrome (ICANS) that does not improve to grade ≤1 within 72 hours with standard of care interventions, and subjects with grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus. Subjects in the expansion cohort who experience ≥ grade 2 CRS or ICANS that remains ≥ grade 2, twenty-four hours after an initial dose of the standard of care treatment may be part of the sub-study of rimiducid. These subjects will receive one of two assigned dose levels. DL1 and DL2 doses are 0.05 mg/kg and 0.01 mg/kg for subjects and DL1: 0.1 mg/kg and DL2: 0.01 mg/kg for subjects with ICANS.

Also known as: Rimiducid

Expansion Cohort iC9-CAR19 cells; Single Arm iC9.CAR19 T cells

Cyclophosphamide DRUG

500 mg/m2/day administered by IV over 3 consecutive days

Also known as: Cytoxan, Neosar

Expansion Cohort iC9-CAR19 cells; Single Arm iC9.CAR19 T cells

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Unless otherwise noted, subjects must meet all of the following criteria to participate in all stages of this study:
• Written informed consent and HIPAA authorization for release of personal health information.
• Adults ≥18 years of age.
• Histologically confirmed B-cell NHL, including the following types defined by WHO 2016:
• Aggressive Lymphomas:
• DLBCL not otherwise specified (NOS)
• T cell/histiocyte rich large B cell lymphoma; primary cutaneous DLBCL, leg type; EBV-positive DLBCL NOS; DLBCL associated with chronic inflammation; Large B-cell lymphoma with IRF4 rearrangement; Intravascular large B-cell lymphoma; ALK-positive large B-cell lymphoma
• Primary mediastinal (thymic) large B-cell lymphoma
• High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; high grade B-cell lymphoma, NOS
• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
• Transformation of indolent lymphoma or CLL to DLBCL will also be included
• Burkitt lymphoma
• Primary CNS lymphoma
• Indolent Lymphomas:
• Follicular lymphoma

You may not qualify if:

• Subject is pregnant or lactating.
• Tumor in a location where enlargement could cause airway obstruction.
• Current use of systemic corticosteroids at doses ≥10mg prednisone daily or its equivalent; those receiving \<10mg daily may be enrolled at the discretion of investigator. Patients with primary CNS lymphoma can receive higher doses of steroids per the investigator's discretion.
• Active infection with HIV, HTLV, HBV, and HCV (can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells) defined as not being well controlled on therapy. Subjects are required to have negative HIV antibody, negative HTLV1 and HTLV2 antibodies, negative Hepatitis B surface antigen, and negative HCV antibody or viral load. In addition, subjects with positive Hepatitis B core antibody will have Hepatitis B viral load tested and subjects with positive Hepatitis B viral load will also be excluded.
• Subject must either have core antibody negative HBV (results can be pending at the time of cell procurement) OR if a subject is hepatitis B core antibody positive they must have their hepatitis B viral load checked. These subjects will be excluded if their viral load is positive at baseline. Subjects who are core antibody positive and viral load negative at baseline will be considered eligible.
• A history of intolerance to fludarabine. Note: subjects with history of intolerance to bendamustine may be considered for enrollment at the discretion of the clinical investigator if they are candidates for lymphodepletion with cyclophosphamide and fludarabine.
• Eligibility criteria to be met prior to procurement:
• Subjects must sign a consent to undergo cell procurement.
• Life expectancy ≥ 12 weeks.
• Evidence of adequate organ function as defined by:
• The following is required within 7 days prior to procurement:
• Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level \>1.5 mg/dL if their conjugated bilirubin is \<1.5× ULN)
• AST ≤ 3 times ULN
• Creatinine Clearance (CrCl) \>30mL/min per Cockcroft and Gault
• Pulse oximetry of \>90% on room air

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead
• UNC Chapel Hill University Cancer Research Fund: collaborator
• The V Foundation: collaborator
• M.D. Anderson Cancer Center: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Related Links

• University of North Carolina Lineberger Comprehensive Cancer Center Clinical Trials

MeSH Terms

Conditions

Lymphoma; Lymphoma, B-Cell; Immune System Diseases; Immunoproliferative Disorders; Lymphatic Diseases; Cytokine Release Syndrome; Neurotoxicity Syndromes

Interventions

Bendamustine Hydrochloride; fludarabine; fludarabine phosphate; AP 1903 reagent; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Hemic and Lymphatic Diseases; Lymphoma, Non-Hodgkin; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Nervous System Diseases; Poisoning; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Phosphoramide Mustards; Phosphoramides; Organophosphorus Compounds

Study Officials

• Natalie Grover, MD

  UNC Lineberger Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 3, 2018
• First Posted: October 5, 2018
• Study Start: March 12, 2019
• Primary Completion: August 31, 2025
• Study Completion (Estimated): July 31, 2040
• Last Updated: December 8, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)