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

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ClinicalTrials.gov Identifier: NCT03016377
Recruitment Status : Recruiting
First Posted : January 10, 2017
Last Update Posted : July 2, 2018
Sponsor:
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

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 many subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome. In this study, to help reduce cytokine release syndrome 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 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. 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 to mild, but still allows the remaining iC9-CAR19 cells to effectively fight the leukemia.

The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable and and later to determine an optimal dose of AP1903 to be given to subjects to alleviate severe cytokine release syndrome.


Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Immune System Diseases Immunoproliferative Disorders Biological: iC9-CAR19 cells Drug: AP1903 Drug: Cyclophosphamide Drug: Fludarabine Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 22, 2018
Estimated Primary Completion Date : November 2021
Estimated Study Completion Date : October 2036


Arm Intervention/treatment
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.
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: AP1903
Subjects who develop grade 4 CRS or grade 2/3 CRS that is unresponsive to standard of care interventions will be given AP1903 at .4 mg/kg.
Other Name: Rimiducid

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




Primary Outcome Measures :
  1. 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). 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. CAR-T-cell-related encephalopathy (CRES) symptoms will be graded according to the criteria outline in Section 12.6 CRES Grading in the protocol and CRS symptoms will be graded according to criteria outlined in Section 12.2 CRS Grading of the protocol.


Secondary Outcome Measures :
  1. 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 12.2 Appendix B: CRS Grading Criteria and Management Guideline. CRES grading criteria outlined in section 12.6 of the protocol.

  2. 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.

  3. 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.

  4. 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)

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   3 Years to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 first CR 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. 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 immunohistochemistry per institutional standards.
  • Life expectancy ≥ 12 weeks.
  • Demonstrate adequate renal and hepatic function as defined in the table below; all screening labs to be obtained within 72 hrs prior to procurement.

    • Serum Creatinine: ≤ 1.5 x ULN
    • Bilirubin: ≤ 1.5 x upper limit of normal (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 is 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.
  • 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.
  • Subjects currently receiving "maintenance" doses of chemotherapy are eligible and the need for intrathecal prophylaxis prior to procurement is left to the discretion of the investigator. Maintenance doses of chemotherapy are defined as methotrexate ≤30 mg/m2/week, mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days. 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 who cannot safely delay definitive treatment for their ALL by at least 4 weeks in the opinion of the investigator.
  • 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 lymphodepleting chemotherapy and cell infusion.
  • Pregnant or breastfeeding.
  • 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, HTLV, HBV, HCV (tests can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells) 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 (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 ≥10mg/day prednisone or its equivalent; those receiving <10mg/day may be enrolled at discretion of investigator. 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 the procurement inclusion criteria 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.
  • 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 hrs prior to lymphodepletion.

    • Serum Creatinine: ≤ 1.5 x ULN
    • Bilirubin: ≤ 1.5 x upper limit of normal (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 is 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 72 hours prior to lymphodepletion.
  • 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.
  • Subjects currently receiving "maintenance" doses of chemotherapy are eligible and the need for intrathecal prophylaxis prior to lymphodepletion is left to the discretion of the investigator. Maintenance chemotherapy is defined as methotrexate ≤30 mg/m2/week, mercaptopurine ≤100 mg/m2/day and vincristine ≤ 2 mg/28 days. For subjects who receive chemotherapy, including intrathecal chemotherapy, that does not fit this definition of maintenance chemotherapy, a two week washout between the last dose of standard of care 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.
  • 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 (ie, two weeks) prior to lymphodepletionn or has received any tumor vaccines within the previous five weeks prior to lymphodepletion.
  • 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 (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.
  • Use of systemic corticosteroids at doses ≥10mg/day prednisone or its equivalent; those receiving <10mg/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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03016377


Contacts
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Contact: Catherine Cheng (919) 445-4208 catherine_cheng@med.unc.edu
Contact: Spencer Laing (919) 445-4208 spencer.laing@med.unc.edu

Locations
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United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Catherine Cheng    919-445-4208    catherine_cheng@med.unc.edu   
Contact: Spencer Laing    (919) 445-4208    spencer.laing@med.unc.edu   
Principal Investigator: Matthew Foster, MD         
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Investigators
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Principal Investigator: Matthew Foster, MD Assistant Professor Hematology-Oncology

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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03016377     History of Changes
Other Study ID Numbers: LCCC 1541-ATL
First Posted: January 10, 2017    Key Record Dates
Last Update Posted: July 2, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
CAR T cells
CD19
Leukemia
T Lymphocytes
AP1903
Cytokine Release Syndrome

Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Immune System Diseases
Immunoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites