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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.

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.

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)

iC9-CAR19 cells

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.

Rimiducid

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

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

Catherine Cheng

Kelly Hoye

Natalie Grover, MD

Natalie S Grover, MD

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.

LCCC1541-ATL is a Phase I/Phase II dose finding trial to determine if chimeric antigen receptor T (CAR-T) cells targeting the CD19 antigen and containing the inducible caspase 9 safety switch can be safely administered to adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia (ALL).

OUTLINE

Cell Procurement

Peripheral blood, up to 300 mL total (in up to 3 collections) will be obtained from subjects for cell procurement. In subjects with inadequate lymphocyte count in the peripheral blood, a leukopheresis may be performed to isolate sufficient T cells. The parameters for apheresis will be up to 2 blood volumes.

Lymphodepleting Regimen

Subjects will receive a lymphodepleting regimen of fludarabine 25 mg/m2/day administered IV over 30 min for three consecutive days and a single IV dose of cyclophosphamide 900 mg/m2 administered over 1 hour on the fourth day. If iC9-CAR19 T cell infusion is delayed for \>4 weeks, lymphodepletion may be repeated prior to iC9-CAR19 T cell infusion.

Administration of iC9-CAR19 T Cells

Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will receive iC9-CAR19 T cells within 2-14 days after completing the pre-conditioning chemotherapy regimen. We will administer iC9-CAR19 post lymphodepletion at dose levels specified. A phase I trial performed by Lee et al established that 1×106 CAR19+ T cells/kg was safe and associated with significant in vivo expansion and we anticipate similar results with iC9-CAR19+ T cells.

Second Cell Infusion Requirements:

Subjects will be offered a second infusion based on B-cell recovery and MRD status \>4 weeks after the initial infusion if cells are available or if the subject has sufficient stored peripheral blood to manufacture additional iC9-CAR19 T cells.

Duration of Therapy

Therapy in LCCC1541-ATL involves 1 infusion of iC9-CAR19 cells. Treatment with one infusion will be administered unless:

* Subject decides to withdraw from study treatment, or
* General or specific changes in the subject's condition render the subject unacceptable for further treatment in the judgment of the investigator.

A second infusion with prior lymphodepletion will be given to subjects enrolled in the expansion cohort and to subjects enrolled in the dose escalation cohort once the RP2D is reached if they meet the eligibility requirements for lymphodepletion and infusion. Specifically, only subjects with the following characteristics will be offered a second infusion:

* B-cell recovery (defined as absolute CD19+ cell count \>50/μL in the blood or bone marrow within 6 months of initial infusion AND/OR
* MRD positive (defined as ≥0.01% as assessed by multi-parameter flow cytometry) with CD19+ expression at any time after the initial infusion.
* \*Note that subjects who receive dose level 1 in the dose escalation will receive the RP2D for their second infusion, if applicable.

Duration of Follow-up

Subjects will be followed for up to 15 years after the final iC9-CAR19 T-cell infusion for RCR evaluation or until death, whichever occurs first. Subjects removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event.

Subjects who receive new therapy (such as hematopoietic stem cell transplant) after a cell product administration will still be required to complete abbreviated follow up procedures.

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

Administration of Autologous CAR-T Cells Targeting the CD19 Antigen and Containing the Inducible caspase9 Safety Switch in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

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).

The recommended phase 2 dose of iC9-CAR19 cells in adult and pediatric subjects will be determined maximum dose at which no more than one out of six patients experiences a dose limiting toxicity (DLT). A DLT is defined according to protocol criteria using the NCI CTCAE, ICANS, and CRS criteria. In general, a DLT is any grade 3 or higher event that is at least possibly related to iC9-CAR19 T cells.

Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in samples of peripheral blood.

ORR (Complete Response/Complete Response with incomplete recovery of counts) to first iC9-CAR19 T cell therapy will be determined using National Comprehensive Cancer Network Response Criteria (NCCN) for acute lymphoblastic leukemia. Assessment of minimal residual disease will be included as criterion of response (ie, the percentage of subjects who achieve CRm \[defined as minimal residual disease negative complete response\] by either flow cytometry or PCR analysis will be determined)

Overall survival will be measured from the date of administration of first iC9-CAR19 T cells to the date of death.

Event free survival rate applies to all subjects and will be measured from the date of administration of first iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from complete response or complete response with incomplete recovery of counts, or death from any cause; subjects not known to have any of these events are censored on the date they were last examined.

Relapse-free survival rate will apply only to subjects achieving complete response or complete response with incomplete recovery of counts and measured from the date of achievement of a remission until the date of relapse or death from any cause; subjects not known to have relapsed or died at last follow-up are censored on the date they were last examined.

The NCI Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a patient-reported outcome measurement system developed to characterize the frequency, severity and interference of 78 symptomatic treatment toxicities.

Patient reported physical functions in adult patients will be assessed per the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health on a five point Likert scale with higher score indicating better functioning.

Patient reported health-related quality of life will be assessed using the PROMIS (Patient-Reported Outcomes Measurement Information System) Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1. PROMIS is a set of person-centered measures, developed by the US Department of Health and Human Services, that evaluates and monitors physical, mental, and social health health on a five point Likert scale with higher score indicating better functioning.

Rate of MRD clearance will be defined as the proportion of subjects who enter MRD-negative complete response (CRm) who are treated with one or two infusions of iC9 CAR19 T cells at the time of being in complete response (CR) or Complete Response with incomplete recovery of counts (CRi), but not CRm.

Spots Global Cancer Trial Database for immune effector cell mediated neurotoxicity syndrome