Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03016377
Recruitment Status : Recruiting
First Posted : January 10, 2017
Last Update Posted : July 2, 2019
Sponsor:
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE January 6, 2017
First Posted Date  ICMJE January 10, 2017
Last Update Posted Date July 2, 2019
Actual Study Start Date  ICMJE March 22, 2018
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells [ Time Frame: 4 weeks ]
Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outline in Section 13.5 Management of Neurotoxicity/Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) for CAR-T Therapy in the protocol and CRS symptoms will be graded according to criteria outlined in Section 13.2 CRS Grading of the protocol.
Original Primary Outcome Measures  ICMJE
 (submitted: January 6, 2017)
Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells [ Time Frame: 6 weeks ]
Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). The iC9-CAR19 T-cells will be considered safe if the proportion of subjects with Grade 3-5 non-infectious, non-hematologic and non-CRS-related toxicities associated with the cell infusion are lower than 0.25 (exceptions include alopecia and electrolyte abnormalities, diarrhea, or nausea and vomiting adverse events that can be managed with supportive care that do not persist as Grade 3-4 toxicities for > 1 week).
Change History Complete list of historical versions of study NCT03016377 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
  • Identify recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in adult and pediatric subjects with relapsed or refractory CD19+ ALL. [ Time Frame: 4 weeks ]
    The recommended phase 2 dose of iC9-CAR19 cells will be determined based on 3+3 dose finding rules and the tolerability of iC9-CAR19 cells assessed by NCI-CTCAE criteria and CRS grading criteria outlined in Section 13.2 Appendix B: CRS Grading Criteria and Management Guideline. ICANS grading criteria outlined in section 13.5 of the protocol.
  • Measure the survival of iC9-CAR19 T cells in vivo as assessed by quantitative polymerase chain reaction (PCR) and flow cytometry. [ Time Frame: 15 years ]
    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.
  • Determine the overall survival after infusion of iC9-CAR19 T cells [ Time Frame: 15 years ]
    Overall survival will be measured from the date of administration of iC9-CAR19 T cells to the date of death.
  • Determine the Overall Response Rate (ORR) (Complete Response/Complete Response with incomplete recovery of counts) mediated by iC9-CAR19 T cell therapy using National Comprehensive Cancer Network Response Criteria (NCCN) for ALL. [ Time Frame: 15 years ]
    ORR (Complete Response/Complete Response with incomplete recovery of counts) to 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)
  • Determine the event-free survival rate by measuring from the date of administration of iC9-CAR19 T cells to the date of signs and symptoms of treatment failure, relapse or death. [ Time Frame: 15 years ]
    Event free survival rate applies to all subjects and will be measured from the date of administration of 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.
  • Determine the relapse-free survival rate by measuring from the date of achievement of a remission until the date of relapse or death from any cause. [ Time Frame: 15 years ]
    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.
  • Measure the patient reported symptoms in adult patients using selected symptoms from the NCI PRO-CTCAE [ Time Frame: 15 years ]
    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.
  • Measure the patient reported physical functions in adult patients using PROMIS Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0. [ Time Frame: 15 years ]
    PROMIS (Patient-Reported Outcomes Measurement Information System) 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
  • Patient reported health-related quality of life in adult patients using the PROMIS Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1. [ Time Frame: 15 years ]
    PROMIS (Patient-Reported Outcomes Measurement Information System) 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
Original Secondary Outcome Measures  ICMJE
 (submitted: January 6, 2017)
  • Measure the survival of iC9-CAR19 T cells in vivo as assessed by quantitative polymerase chain reaction (PCR) and flow cytometry. [ Time Frame: 15 years ]
    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.
  • Determine the overall survival after infusion of iC9-CAR19 T cells [ Time Frame: 15 years ]
    Overall survival will be measured from the date of administration of iC9-CAR19 T cells to the date of death.
  • Determine the Overall Response Rate (ORR) (Complete Response/Complete Response with incomplete recovery of counts) to iC9-CAR19 T cell therapy using National Comprehensive Cancer Network Response Criteria (NCCN) for acute lymphoblastic leukemia. [ Time Frame: 15 years ]
    ORR (Complete Response/Complete Response with incomplete recovery of counts) to 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)
  • Determine the event-free survival rate by measuring from the date of administration of iC9-CAR19 T cells to the date of signs and symptoms of treatment failure, relapse or death. [ Time Frame: 15 years ]
    Event free survival rate applies to all subjects and will be measured from the date of administration of 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.
  • Determine the relapse-free survival rate by measuring from the date of achievement of a remission until the date of relapse or death from any cause. [ Time Frame: 15 years ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: January 6, 2017)
  • The number of patients with adverse events as a measure of safety and tolerability of escalating doses of AP1903 [ Time Frame: 72 hours ]
    Toxicity will be classified and graded according to the NCI-CTCAE, version 4.0. The optimal dose will be determined separately in adult and pediatric subjects. The optimal dose will exhibit a drug-related dose limiting toxicity rate that is <0.25 and also maximizes the proportion of subjects with Grade 2*/3 CRS symptoms who experience CRS symptom resolution to ≤ Grade 1 after AP1903 administration without compromising the anti-leukemia activity of iC9-CAR19 cells.
  • Determine the Overall Response Rate (ORR) (Complete Response/Complete Response with incomplete recovery of counts) to iC9-CAR19 T cell therapy in patients treated with AP1903 using National Comprehensive Cancer Network Response Criteria (NCCN). [ Time Frame: 15 years ]
    ORR (Complete Response/Complete Response with incomplete recovery of counts) will be determined using NCCN Response Criteria for acute lymphoblastic leukemia. Analysis 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).
  • Determination of serum cytokine levels after iC9-CAR19 T cell infusion after receipt of AP1903 to treat signs/symptoms of cytokine release syndrome. [ Time Frame: 24 hours ]
    Serum cytokine levels will be determined by established methods (enzyme-linked immunosorbent assay; ELISA).
  • Measure the survival of iC9-CAR19 T cells in vivo in patients treated with AP1903 as assessed by quantitative polymerase chain reaction (PCR) and flow cytometry. [ Time Frame: 15 years ]
    Persistence of iC9-CAR19 T cells in vivo will be determined by quantitative PCR and flow cytometry in peripheral blood samples.
  • Determine the overall survival after infusion of iC9-CAR19 T cells in patients who have received AP1903 to treat cytokine release syndrome. [ Time Frame: 15 years ]
    Overall survival will be measured from the date of administration of iC9-CAR19 T cells to the date of death.
  • Determine the event-free survival rate in patients who have received AP1903 by measuring from the date of administration of iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse or death. [ Time Frame: 15 years ]
    Event free survival applies to all subjects and will be measured from the date of administration of 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
  • Determine the relapse-free survival rate in patients who have received AP1903 by measuring from the date of achievement of a remission until the date of relapse or death from any cause. [ Time Frame: 15 years ]
    Relapse free survival 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.
 
Descriptive Information
Brief Title  ICMJE Administration of Autologous CAR-T CD19 Antigen With Inducible Safety Switch in Patients With Relapsed/Refractory ALL
Official Title  ICMJE 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
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 your 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 aract as e signals to other cells and are the way cells talk to one another. During cytokine release syndromesyndrome, 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). If you experience severe cytokine release syndrome or moderate to severe cytokine release syndrome that does not get better once you are given standard treatments, you may be given a second study drug called rimiducid. Similar studies showed that rimiducid can to turn on the safety switch, iC9 in other therapies. Using rimiducid to activate the safety switch may be done in addition to treating you according to hospital guidelines and making all efforts to immediately attend to your cytokine release syndrome symptoms

Detailed Description

STUDY OBJECTIVES

Primary Objective

- To determine the safety and tolerability of autologous iC9-CAR19 T cells administered to adult and pediatric subjects with relapsed or refractory CD19+ ALL.

Secondary Objectives

  • To identifty a recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in adult and pediatric subjects with relapsed or refractory CD19+ ALL.
  • To measure the survival of iC9-CAR19 T cells in vivo.
  • To determine the anti-leukemia overall response rate (ORR) mediated by autologous iC9-CAR19 T cells administered to adult and pediatric subjects with relapsed or refractory CD19+ ALL.
  • To determine overall survival (OS) in adult and pediatric subjects with relapsed or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.
  • To determine event-free survival (EFS) in adult and pediatric subjects with relapsed or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.
  • To determine relapse-free survival (RFS) in adult and pediatric subjects with relapsed or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.
  • To measure patient-reported symptom, physical function, and health-related quality of life at baseline and over time in adult subjects treated with iC9-CAR19 T cells.

Exploratory objectives

  • To determine the utility of the safety switch in iC9-CAR19 T cells by allowing for administration of rimidicid (0.4 mg/kg dose) to subjects with grade 4 CRS or grade 3 CRS that is unresponsive to standard of care interventions (i.e., does not resolve to grade 0-1 within 24 hours after 2 doses of tocilizumab, with sum of doses ≥12mg/kg) and to subjects who develop grade ≥3 ICANS that does not improve to grade ≤1 within 72 hours with standard of care interventions or grade 4 ICANS of any duration with evidence of cerebral edema and/or generalized convulsive status epilepticus following infusion of iC9-CAR19 cells to adult and pediatric subjects with relapsed or refractory CD19+ ALL.
  • To explore whether changes observed on a brief cognitive assessment are associated with the occurrence of CRS or neurotoxicity from iC9-CAR19 T cells.
  • To explore feasibility of ocular ultrasound measurement of optic nerve sheath diameter in adult participants only, and associations with clinical grading of CRES.
  • To determine whether there are correlations between CAR T cell behavior and the integration locations of CAR.CD19.

ENDPOINTS

Primary Endpoint

- Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5), ICANS symptoms will be graded according to the criteria outlined in Appendix E and CRS symptoms will be graded according to criteria outlined in Appendix B.

(Note: The safety evaluation period for DLT assessment will encompass toxicities related to the cell therapy that are experienced starting on the day of iC9-CAR19 T cell infusion up through 4 weeks post infusion. See section 5.1.2 of the protocol for definitions of DLTs and RP2D. General safety monitoring will begin at the time of procurement).

Secondary Endpoints

  • The recommended phase 2 dose of iC9-CAR19 cells will be determined based on 3+3 dose finding rules as specified in section 5.1.1 and the tolerability of iC9-CAR19 cells assessed by NCI-CTCAE criteria, ICANS grading criteria outlined in Appendix E and CRS grading criteria outlined in Appendix B.
  • 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 (CR/CRi) to iC9-CAR19 T cell therapy will be determined using National Comprehensive Cancer Network Response Criteria (NCCN) for ALL provided in Section 8.5.1. Assessment of MRD will be included as criterion of response (i.e., the percentage of subjects who achieve CRm defined as MRD negative CR by either flow cytometry or PCR analysis will be determined).
  • OS will be measured from the date of administration of iC9-CAR19 T cells to the date of death.
  • EFS applies to all subjects and will be measured from the date of administration of iC9-CAR19 T cells to the date of signs and symptoms of treatment failure or relapse from CR or CRi, or death from any cause; subjects not known to have any of these events are censored on the date they were last examined.
  • RFS will apply only to subjects achieving CR or CRi 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.
  • Patient reported symptoms will be measured using selected symptoms from the NCI PRO-CTCAE. Patient-reported physical function will be measured using the PROMIS Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0. Patient-reported health-related quality of life will be measured using the PROMIS Global Health Score derived from the PROMIS Global Health Short Form v1.0-1.1. (see Appendix D).

Exploratory Endpoints

  • The efficacy of rimiducid (0.4 mg/kg) will be assessed by pre to post dose diminutions in iC9-CAR19 cell viability in vivo, cytokine production, and CRS symptom grade to 0-1 per criteria provided in Appendix B.
  • Cognitive function will be assessed by the ICE score [49] (score 0-10) (see Appendix E) pre- and post- infusion of iC9-CAR19 T cells during the 4-week safety evaluation period after cell infusion.
  • Optic nerve sheath diameter will be measured in millimeters using ocular ultrasound.
  • RNAseq and DNA analysis will be used to determine CAR.CD19 integration locations in the CAR T cell products and in the peripheral blood within the first 15 years after cell infusion. It will be determined if there is a correlation between the integration location and CAR T cell behavior.

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.

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.

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.

Duration of Follow-up

Subjects will be followed for up to 15 years 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Lymphoblastic Leukemia
  • Immune System Diseases
  • Immunoproliferative Disorders
Intervention  ICMJE
  • Biological: iC9-CAR19 cells
    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)
    Other Name: CAR.CD19 T cells
  • Drug: Rimiducid
    Subjects who develop grade 4 CRS or grade 2/3 CRS that is unresponsive to standard of care interventions will be given Rimiducid at .4 mg/kg.
    Other Name: AP1903
  • Drug: Cyclophosphamide
    900 mg/m^2 IV over 1 hour on day 4 of lymphodepleting chemotherapy.
    Other Name: Neosar
  • Drug: Fludarabine
    25 mg/m^2/day IV over 30 minutes administered for 3 consecutive days.
    Other Name: Fludara
Study Arms  ICMJE Experimental: iC9-CAR19 cells
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.
Interventions:
  • Biological: iC9-CAR19 cells
  • Drug: Rimiducid
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 6, 2017)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2036
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria - Cell Procurement

  • Written informed consent for procurement signed by subject or legal guardian of a pediatric subject and HIPAA authorization for release of personal health information.
  • 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.
  • Relapsed or refractory precursor B cell ALL:

    • Second or greater bone marrow relapse, or
    • Any bone marrow relapse >100 days after allogeneic stem cell transplant, or
    • 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 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 relapses or primary refractory ALL are met and the biopsy for extramedullary disease confirms CD19 expression
    • For pediatric subjects: first bone marrow or isolated non-CNS extramedullary relapse refractory to 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.
    • Subjects with CNS2 disease and concurrent bone marrow relapse will be eligible. Intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion
  • Subjects with Ph+ ALL will be eligible if they have failed ≥2 ABL tyrosine kinase inhibitors or relapsed after allogeneic stem cell transplant. Subjects with the T315I ABL kinase point mutation will be eligible if they have failed ponatinib-containing therapy, regardless of the number of prior ABL tyrosine kinase inhibitors.
  • CD19 positivity of lymphoblasts confirmed by flow cytometry or IHC per institutional standards.
  • Life expectancy ≥12 weeks.
  • Demonstrate adequate renal and hepatic function as defined in the table below:

System Laboratory Value Renal*: Serum Creatinine ≤ 1.5 × ULN Hepatic: Total bilirubin ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome; Aspartate aminotransferase (AST) ≤ 3.0 × ULN; Alanine aminotransferase (ALT) ≤ 3.0 × ULN *For pediatric patients, adequate renal function defined below: Age: Maximum Serum Creatinine (mg/dL) (Male, Female) 3 to <6 years: ≤0.8, ≤0.8; 6 to <10 years: ≤1, ≤1; 10 to <13 years: ≤1.2, ≤1.2; 13 to <16 years: ≤1.5, ≤1.4; 16 to <18 years: ≤1.7, ≤1.4

  • 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.
  • Subjects currently receiving "maintenance" doses of chemotherapy are eligible and the need for intrathecal prophylaxis prior to procurement is to the discretion of the investigator. Maintenance doses of systemic chemotherapy are defined as methotrexate ≤30 mg/m2/week, mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days. Maintenance therapy in patients with Ph+ leukemia may also contain tyrosine kinase inhibitors (TKIs) targeting BCR-ABL, at the discretion of the investigator. Corticosteroid-containing maintenance therapy is permitted only if corticosteroids are administered >14 days prior to procurement.

Exclusion Criteria - Cell Procurement

  • 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.
  • Lumbar puncture must be performed prior to procurement and subjects with evidence of CNS3 disease will be excluded from study entry. Subjects with concurrent CNS3 disease and bone marrow relapse who have responded to CNS-directed therapy prior to enrollment/lymphodepletion will be allowed to participate. Subjects with CNS2 disease and concurrent bone marrow relapse will be eligible. 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, 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, HTLV, HBV, HCV. Note: To meet eligibility subjects are required to be negative for HIV antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2, 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 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. 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 in inclusion 4.1.12 within 2 weeks of procurement.

Inclusion Criteria - Lymphodepletion

  • Written informed consent for the main study signed by subject or legal guardian of a pediatric subject.
  • Relapsed or refractory precursor B cell ALL, confirmed by presence of blasts in the blood or bone marrow (≥5%) or in any extramedullary site.
  • Karnofsky score >60%, if ≥16 years old, or Lansky performance score of greater than 60% if <16 years old .
  • 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.
  • Demonstrate adequate renal and hepatic function as defined in the table below; all screening labs to be obtained within 72 hours prior to lymphodepletion.

System Laboratory Value Renal*: Serum Creatinine ≤1.5 × ULN Hepatic: Total bilirubin ≤1.5 × ULN, unless attributed to Gilbert's Syndrome; AST ≤ 3.0 × ULN; ALT ≤3.0 × ULN

*For pediatric patients, adequate renal function defined below: Age: Maximum Serum Creatinine (mg/dL) (Male, Female) 3 to <6 years: ≤0.8, ≤0.8; 6 to <10 years: ≤1, ≤1; 10 to <13 years: ≤1.2, ≤1.2; 13 to <16 years: ≤1.5, ≤1.4; 16 to <18 years: ≤1.7, ≤1.4

  • Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to lymphodepletion. Note: Females are considered of child bearing potential unless they are premenarchal, surgically sterile 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.
  • For subjects who receive chemotherapy between cell procurement and lymphodepletion, washout periods as described in exclusion criteria sections 4.4.5 to 4.4.11 between chemotherapy and the beginning of lymphodepletion will be required.
  • Subjects must have autologous transduced activated T cells that meet the Certificate of Analysis (CofA) acceptance criteria.

Exclusion Criteria - Lymphodepletion

  • 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.
  • Treatment with any investigational drug within 14 days prior to lymphodepletion or has received any tumor vaccines within the previous five weeks prior to lymphodepletion.
  • Subject has received pegylated-asparaginase ≤3 weeks prior to lymphodepletion.
  • Radiotherapy to a non-CNS site completed <1 week prior to lymphodepletion, or CNS directed radiation completed <7 weeks prior to lymphodepletion.
  • Subject is receiving following drugs <1 week prior to lymphodepletion: salvage chemotherapy (e.g. clofarabine, cytosine arabinoside >100 mg/m2, anthracyclines, cyclophosphamide, methotrexate ≥25 mg/m2).
  • Any systemic drug used for GVHD must be stopped >3 weeks prior to lymphodepletion (e.g. calcineurin inhibitors, methotrexate or other chemotherapy drugs, mycophenolyate, rapamycin, thalidomide, or immunosuppressive antibodies such as anti-CD20 (rituximab), anti-TNF, anti-IL6 or anti-IL6R, systemic steroids).
  • The following drugs must be stopped prior to the beginning of lymphodepleting chemotherapy: tyrosine kinase inhibitors, hydroxyurea, vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate <25 mg/m2, cytosine arabinoside <100 mg/m2/day, and asparaginase (non-pegylated). These drugs should not be administered concomitantly or following lymphodepleting chemotherapy.
  • CNS prophylaxis with intrathecal methotrexate, cytarabine and/or hydrocortisome treatment must be stopped prior to lymphodepleting chemotherapy.
  • Patients with the following systemic viral infections will be excluded: active HIV, HTLV, HBV, HCV. Note: To meet eligibility subjects are required to be negative for HIV antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2, 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 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.
  • 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. Physiologic replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent.

Inclusion Criteria- iC9-CAR19 Cell Infusion

  • Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use 2 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.

Exclusion Criteria- iC9-CAR19 Cell Infusion

  • Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary (e.g., to treat CRS).
  • Severe systemic uncontrolled disease or toxicities that develop after lymphodepletion may prompt exclusion from cell infusion at the discretion of the investigator.
  • Received any donor lymphocyte infusions (DLI) ≤6 weeks prior to iC9-CAR19 T cell product administration.
  • Received any T cell lytic or toxic antibody (e.g. alemtuzumab) ≤8 weeks prior to iC9-CAR19 T cell product administration (residual lytic levels may destroy the infused iC9-CAR19 T cells and/or prevent their in vivo expansion).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 70 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Catherine Cheng (919) 445-4208 catherine_cheng@med.unc.edu
Contact: Spencer Laing (919) 445-4208 spencer.laing@med.unc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03016377
Other Study ID Numbers  ICMJE LCCC 1541-ATL
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party UNC Lineberger Comprehensive Cancer Center
Study Sponsor  ICMJE UNC Lineberger Comprehensive Cancer Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Matthew Foster, MD Assistant Professor Hematology-Oncology
PRS Account UNC Lineberger Comprehensive Cancer Center
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP