Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL

NCT03016377 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: LCCC1541-ATL
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

The body has different ways of fighting infection and disease. No single way is effective at fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding those bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to try to create a more effective treatment. This investigational treatment is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. In previous studies, it has been shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. A gene is a unit of DNA. Genes make up the chemical structure carrying the genetic information that may determine human characteristics (i.e., eye color, height and sex). The new gene that is put in the T cells makes a piece of an antibody called anti-CD19. This antibody can flow through the blood and can find and stick to leukemia cells because these leukemia cells have a substance on their surface called CD19. Anti-CD19 antibodies have been used to treat people with leukemia but have not been strong enough to cure most patients. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood a piece of it is now joined to the surface of the T cells. Only the part of the antibody that sticks to the leukemia cells is attached to the T cells instead of the entire antibody. 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 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 of giving ATLCAR.CD19 cells to leukemia patients have been encouraging; however, many subjects receiving this treatment have experienced unwanted side effects including neurotoxicity and/or cytokine release syndrome (also referred to as cytokine storm or an infusion reaction). Cytokines are small proteins that interreact as e signals to other cells and are the way cells talk to one another. During cytokine release syndrome, too many cytokines are released and too many cells in your body react to their release. Symptoms resulting from cytokine release syndrome vary from flu-like symptoms to more severe side effects such as cardiac arrest, multi-system organ failure or death. We predict that about 50% of patients on this study will experience mild to severe cytokine release syndrome. To help reduce cytokine release syndrome symptoms in future patients, a safety switch has been added to the ATLCAR.CD19 cells that can cause the cells to become dormant or "go to sleep". The safety switch is called inducible caspase 9 or iC9. The modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. The purpose of this study is to determine whether receiving the iC9-CAR19 cells is safe and tolerable (there are not too many unwanted effects). Researchers has previously tested different doses of the iC9-CAR19. An effective dose that had the least number of unwanted side effects in patients was identified. It was planned to test this dose in more patients to learn more about its effect in the body. This type of research study is called a dose expansion study. It will allow the investigators to collect more information about the effect of this dose in treating of certain type of cancer.

Conditions

Acute Lymphoblastic Leukemia; Immune System Diseases; Immunoproliferative Disorders

Keywords

CAR T cells; CD19; Leukemia; T Lymphocytes; AP1903; Cytokine Release Syndrome; Rimiducid; ICANS; Immune effector cell mediated neurotoxicity syndrome

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 (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).

  4 weeks

Secondary Outcomes (11)

• Incidence of dose limiting toxicity to identify recommended phase 2 dose (RP2D)

  4 weeks

• Changes in persistence of iC9-CAR19 T cells in vivo

  15 years

• Overall Response Rate (ORR)

  15 years

• Overall survival after infusion of iC9-CAR19 T cells

  15 years

• Event-free survival rate

  15 years

Study Arms (2)

iC9-CAR19 cells

EXPERIMENTAL

The 3+3 design in adult subjects and an independent study using 3+3 design in pediatric subjects. The starting dose of 5 x 10\^5 transduced cells/kg will enroll 3 adult subjects in the initial cohort. If there are no dose limiting toxicities w/in 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 1 x10\^6 transduced cells/kg in adults. If there is toxicity in 1/3 patients in the initial cohort, the cohort will be expanded to enroll up to 6 adult patients. If the dose level 1 is determined to be above the tolerated cell dose, de-escalation would occur to dose level -1 where subjects would receive 1 x 10\^5 transduced cells/kg. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before administration of iC9-CAR19 T cells.

Biological: iC9-CAR19 cells; Drug: Rimiducid; Drug: Cyclophosphamide; Drug: Fludarabine

Expansion Cohort Second Administration of iC9-CAR19 cells

EXPERIMENTAL

After the recommended phase 2 dose (RP2D) of iC9-CAR19 T cells has been determined in adults, up to 18 additional adult subjects will be enrolled in an expansion cohort at the RP2D. In the expansion cohort, subjects will be offered a second infusion of iC9-CAR19 T cells based on B-cell recovery and minimal residual disease (MRD) status. All subjects will receive a lymphodepleting regimen of fludarabine and cyclophosphamide before second administration of iC9-CAR19 T cells. Subjects in the expansion cohort who experience ≥grade 2 CRS or ICANS, did not respond to the initial dose of the standard of care treatment will be enrolled in a sub-study of rimiducid.

Biological: iC9-CAR19 cells; Drug: Rimiducid; Drug: Cyclophosphamide; Drug: Fludarabine

Interventions

iC9-CAR19 cells BIOLOGICAL

Three dose levels are being evaluated: dose level -1 (1 x 10\^5), dose level 1 (5 x 10\^5), and dose level 2 ( 1x 10\^6)

Also known as: CAR.CD19 T cells

Expansion Cohort Second Administration of iC9-CAR19 cells; iC9-CAR19 cells

Rimiducid DRUG

Subjects with CRS and ICAN will assign one of two dose levels (DL)s of rimiducid with the standard treatment: 0.05 mg/kg or 0.1 mg/kg for subjects with CRS and 0.01mg/kg or 0.1mg/kg for subjects with ICAN. Subjects will first be enrolled on DL 1 and then enrolled on DL 2, and 0.4mg/kg rimiducid will be given to subjects who did not respond to the initial dose.

Also known as: AP1903

Expansion Cohort Second Administration of iC9-CAR19 cells; iC9-CAR19 cells

Cyclophosphamide DRUG

900 mg/m\^2 IV over 1 hour on day 4 of lymphodepleting chemotherapy.

Also known as: Neosar

Expansion Cohort Second Administration of iC9-CAR19 cells; iC9-CAR19 cells

Fludarabine DRUG

25 mg/m\^2/day IV over 30 minutes administered for 3 consecutive days.

Also known as: Fludara

Expansion Cohort Second Administration of iC9-CAR19 cells; iC9-CAR19 cells

Eligibility Criteria

• Age: 3 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent for procurement signed by the subject or the legal guardian of a pediatric subject and HIPAA authorization
• Age 3 to 17 years of age for pediatric subjects (weight must be ≥10 kg), ≥ 18 to 70 years of age for adults at the time of consent.
• Karnofsky score \> 60%, if ≥16 years old, or Lansky performance score of greater than 60% if \<16 years old .
• Demonstrate adequate renal and hepatic function as defined below; all screening labs to be obtained within 72 hours prior:
• System Laboratory Value Renal\* Serum Creatinine (sCr) ≤ 1.5 × ULN) Hepatic: Total bilirubin (tBili) ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome Aspartate aminotransferase (AST) ≤ 3.0 × ULN Alanine aminotransferase (ALT) ≤ 3.0 × ULN
• Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to procurement. Note: Females are considered of childbearing potential unless they are premenarchal, surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use two forms of effective methods of contraception from the time of informed consent until 3 months after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Female participants will inform their male partners that they must use the methods of birth control required by the protocol.
• Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the last dose of study therapy. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures.
• Relapsed or refractory precursor B cell ALL:
• nd or greater bone marrow or central nervous system (CNS) relapse,
• Any bone marrow or CNS relapse \>100 days after allogeneic stem cell transplant, Primary refractory ALL defined as no complete response after 2 cycles of a standard of care chemotherapy regimen, or
• For adult subjects: first bone marrow or CNS relapse with duration of first CR \<1 year, or CR1 duration ≥1 year and refractory to ≥1 cycle of therapy for treatment of relapse
• Subjects with isolated non-CNS extramedullary disease will be eligible as long as the time-of-remission criteria above for bone marrow and CNS relapses or primary refractory ALL are met and the biopsy for extramedullary disease confirms CD19 expression
• For pediatric subjects: first bone marrow, CNS or isolated non-CNS extramedullary relapse refractory to more than 1 cycle of standard therapy for relapsed ALL
• While active CNS3 leukemia will be excluded, subjects with concurrent CNS3 disease and bone marrow relapse who have responded to CNS-directed therapy prior to enrollment will be allowed to participate. Intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion.

You may not qualify if:

• Subjects meeting any of the following criteria cannot be enrolled in this study:
• Subjects with relapsed fulminant CD19+ ALL that is rapidly progressing with circulating lymphoblasts that are rising in proportion to \>50% of circulating white blood cells.
• Intrathecal chemotherapy will be allowed to continue between cell procurement and lymphodepleting chemotherapy.
• Pregnant or breastfeeding (Note: breast milk cannot be stored for future use if the milk is collected while the mother is being treated on study).
• Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years.
• Subjects must not have tumor in a location where enlargement could cause airway obstruction.
• Subjects may not have an oxygen requirement as defined by pulse oximetry of \<90% on room air.
• Subjects must not have left ventricular ejection fraction of \<40% (shortening fraction \<27% for pediatric subjects) as measured by echocardiogram or MUGA.
• Patients with the following systemic viral infections will be excluded: active HIV, HBV, HCV. Only subjects meeting the criteria as so described will be infused. Note: To meet eligibility subjects are required to be negative for HIV antibody or HIV viral load, negative for Hepatitis B surface antigen, or negative for HCV antibody or HCV viral load
• Patients who are on treatment for other active uncontrolled infections (not referenced above) with resolution of signs/symptoms are not excluded. Non-influenza, non-RSV, isolated upper respiratory infections are not excluded. Other active uncontrolled infections will be excluded.
• Prior to procurement current use of systemic corticosteroids at doses ≥10 mg/day prednisone or its equivalent; those receiving \<10 mg/day may be enrolled at discretion of investigator. (Note: Corticosteroid use with doses at the discretion of the treating physician are allowed after procurement up to the beginning of lymphodepletion. Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary e.g., to treat CRS).
• Physiologic replacement with hydrocortisone is allowed at doses 6-12 mg/m2/day, or equivalent.
• Received anti-CD19 antibody-based therapy or cytotoxic chemotherapy not described as maintenance therapy (within 2 weeks of procurement per section).
• Life expectancy ≥ 12 weeks.
• Subjects who have received prior therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion on this study.

Sponsors & Collaborators

• UNC Lineberger Comprehensive Cancer Center: lead
• Bellicum Pharmaceuticals: collaborator
• The Leukemia and Lymphoma Society: 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

• Related Info

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Immune System Diseases; Immunoproliferative Disorders; Leukemia; Cytokine Release Syndrome

Interventions

AP 1903 reagent; Cyclophosphamide; fludarabine; fludarabine phosphate

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Natalie S 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: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 6, 2017
• First Posted: January 10, 2017
• Study Start: March 22, 2012
• Primary Completion: September 12, 2025
• Study Completion (Estimated): September 12, 2037
• Last Updated: October 27, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)