Patient case: 4-year-old female with leukemia; genetic feature: ABL1

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

Summary: This research study combines two different ways of fighting disease: antibodies and T cells. 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 is designed to combine both T cells and antibodies in order to create a more effective treatment. The treatment that is being researched 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. 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, then the subject may take part in a sub-study where you will be given a second study drug, AP1903. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The goal of the sub-study 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 to determine an optimal dose of AP1903 to be given to subjects to alleviate severe cytokine release syndrome.

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+ acute lymphoblastic leukemia. All subjects will receive a dose of 1X10^6 cells/kg of iC9-CAR19 T cells
  Secondary Objectives
  -  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+ acute lymphoblastic leukemia.
  -  To determine overall survival (OS) in adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia following infusion of IC9-CAR19 T cells.
  -  To determine event-free survival (EFS) in adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia following infusion of IC9-CAR19 T cells.
  -  To determine relapse-free survival (RFS) in adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia following infusion of IC9-CAR19 T cells
  Sub-Study Objectives
  Adult subjects who develop Grade 2* CRS or adult and pediatric subjects who develop Grade 3 CRS as a consequence of iC9-CAR19 therapy will enter a sub-study designed to evaluate the safety and the optimal dose of AP1903 that can be administered to adult and pediatric subjects with CD19+ acute lymphoblastic leukemia that provides adequate CRS symptom relief will be determined separately in adult and pediatric subjects. Five potential doses of AP1903 (range 0.025 mg/kg to 0.4 mg/kg) will be evaluated in the sub-study. All subjects who develop Grade 4 CRS will be treated per standard of care guidelines.
  -  The optimal dose will be estimated based on isotonic estimates of CRS control, anti-leukemia response and dose limiting toxicity (DLT) rates. The estimated optimal dose is the lowest dose that maximizes the probability of anti-leukemia response and CRS control among doses with dose limiting toxicity rate not exceeding 0.25.
  Primary Objective of Sub-Study
  To evaluate the safety of AP1903 and determine the optimal dose or doses that can be administered to adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia that can alleviate Grade 2*/3 CRS symptoms to ≤ Grade 1 without compromising the anti-leukemia response mediated by autologous iC9-CAR19 T cell therapy.
  Secondary Objectives of Sub-Study
  -  To determine the anti-leukemia ORR to iC9-CAR19 T cell infusion therapy in adult, and pediatric subjects with relapsed/refractory CD19+ acute lymphoblastic leukemia who received doses of AP1903 to treat Grade 2*/3 signs/symptoms of cytokine release syndrome.
  -  To determine serum cytokine levels after iC9-CAR19 T cell infusion in adult and pediatric subjects with relapsed/refractory CD19+ acute lymphoblastic leukemia who received doses of AP1903 to treat signs/symptoms of Grade 2*/3 cytokine release syndrome.
  -  To measure iC9-CAR19 T cells in the peripheral blood of adult and pediatric subjects with relapsed/refractory CD19+ acute lymphoblastic leukemia following escalating doses of AP1903 to treat signs/symptoms of Grade 2*/3 cytokine release syndrome.
  -  To measure iC9-CAR19 T cells in the peripheral blood of adult and pediatric subjects with relapsed/refractory CD19+ acute lymphoblastic leukemia following escalating doses of AP1903 to treat signs/symptoms of Grade 2*/3 cytokine release syndrome. To determine EFS in adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia following the administration of escalating doses of AP1903 to treat signs/symptoms of Grade 2*/3 cytokine release syndrome.
  -  To determine relapse-free survival rate in adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia following the administration of escalating doses of AP1903 to treat signs/symptoms of Grade 2*/3 cytokine release syndrome.
  ENDPOINTS
  Primary Endpoint
  Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 4.0).
  (Note: The safety evaluation period will encompass toxicities related to the cell therapy that are experienced starting on the day of iC9-CAR19 T cell infusion up through 6 weeks post infusion. The iC9-CAR19 T-cells will be considered safe if the proportion of subjects with Grade 3-5 non-infectious, non-hematologic and non-cytokine release syndrome-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).
  Secondary Endpoints
  -  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 acute lymphoblastic leukemia provided in Section 7.8.1. 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 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 complete remission 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.
  -  Relapse free survival 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.
  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 low (CD3 count as assayed by flow cytometry less than 200/μl) T-cell count in the peripheral blood, a leukopheresis may be performed to isolate sufficient T cells. The parameters for pheresis will be 2 blood volumes.
  iC9-CAR19 Cells Administration
  Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will receive iC9-CAR19 T cells within 2-4 days after completing the pre-conditioning chemotherapy regimen. We will administer iC9-CAR19 post lymphodepletion at a dose of 1×106 iC9-CAR19+ T cells/kg.
  Subjects may receive re-infusion of IC9-CAR19 T cells (without lymphodepleting chemotherapy) if the following criteria are met:
  -  The subject has completed the 6 week evaluation period post initial infusion AND:
  -  The subject does not have progressive leukemia AND:
  -  The subject has sufficient stored cells for re-infusion (1x10^6/kg) AND
  -  Either has been treated with AP1903 or corticosteroids for CRS, OR has evidence of loss of iC9-CAR19-cell persistence or function.
  Duration of Therapy
  Therapy in LCCC1541-ATL involves 1-3 infusions of iC9-CAR19 cells (see section 5.3.3). Treatment with at least 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.
  Cytokine Release Syndrome Sub-Study Therapy
  Subjects who are eligible for the sub-study, designed to determine the safety and optimal dose(s) of AP1903 that can be administered to adult or pediatric subjects with CD19+ acute lymphoblastic leukemia that reduces CRS symptoms to ≤ Grade 1 in all subjects treated at that dose level while simultaneously preserving the anti-leukemia response rate mediated by autologous iC9-CAR19 T cell therapy, may receive up to two doses of AP1903 over a 48-hr period administered 24 hrs apart. The planned dose levels of AP1903 that will be tested are 0.025mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg and 0.4 mg/kg. If CRS symptoms have not improved to ≤ Grade 1 within 24 hrs of receiving a 1st or 2nd dose of AP1903 or become worse (e.g., progress to Grade 4) during the sub-study, then these subjects will be classified as non-responders and treated for CRS according to standard of care guidelines.
  Duration of Follow-up
  Subjects will be followed for up to 15 years for replication-competent retrovirus 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.

Eligibility: All clinical and laboratory data required for determining eligibility must be available in the subject's medical/research record which will serve as the source document. Subjects may be transfused with blood to obtain a hemoglobin level >8.0 g/dL and platelet count > 20,000 per µl.
  Note: During the period after cell procurement and during iC9-CAR19 T-cell production, subjects are allowed to receive standard of care therapy for acute lymphoblastic leukemia to manage their disease if the treating physician feels it is in the subject's best interest.
  Inclusion Criteria:
  -  Written informed consents signed by subject or legal guardian of a pediatric subject and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Subjects must sign a consent to undergo cell procurement. Written informed consent to enroll in the iC9-CAR19 cell therapy trial must be obtained prior to lymphodepletion.
  -  Age 1 to 17 years of age for pediatric subjects (weight must be ≥ 10 kg), ≥ 18 years of age for adults at the time of consent.
  -  Karnofsky score > 60% if > 10 years old or Lansky performance score of greater than 60% if ≤ 10 years old.
  -  Diagnosis of CD19+ acute lymphoblastic leukemia (by immunohistochemistry (IHC) or flow cytometry) with persistent or relapsed disease as defined by ≥ 5% lymphoblasts in the blood or marrow, or biopsy-proven, non central nervous system extramedullary infiltration of lymphoblasts.
  -  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 enrollment/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 procurement.
  -  Serum Creatinine: < 3 x upper limit of normal (ULN)
  -  Bilirubin: < 3 × upper limit of normal
  -  Aspartate Aminotransferase (AST): < 5 × upper limit of normal
  -  Alanine aminotransferase (ALT): < 5 × upper limit of normal
  -  Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to procurement and again 72 hours prior to iC9-CAR19 T cell infusion. NOTE: Females are considered of child bearing potential unless they are 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 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 or lymphodepleting 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. (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).
  -  To Qualify for Autologous T Lymphocyte (ATL) Cell Infusion:
  -  Subjects must have autologous transduced activated T-cells with ≥ 80% expression of CAR19
  -  Bilirubin ≤1.5 times the upper limit of normal (ULN)
  -  AST ≤ 3 times ULN
  -  Serum creatinine ≤1.5 times ULN
  -  Pulse oximetry of > 90% on room air
  Exclusion Criteria:
  -  Subjects with relapsed fulminant CD19+ acute lymphoblastic leukemia that is rapidly progressing who cannot safely delay definitive treatment for their acute lymphoblastic leukemia by at least 4 weeks in the opinion of the investigator.
  -  Lumbar puncture must be performed prior to enrollment and subjects with evidence of central nervous system disease will be excluded from study entry.
  -  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 a history of hypersensitivity reactions to murine protein-containing products.
  -  Subject must not have a known sensitivity to mouse monoclonal antibodies.
  -  Treatment with any investigational drug within 21 days (ie, three weeks) prior to ATL infusion or has received any tumor vaccines within the previous six weeks prior to ATL infusion.
  -  Subjects must not have left ventricular ejection fraction of <40% (shortening fraction <27% for pediatric subjects) as measured by echocardiogram or multigated acquisition (MUGA).
  -  Active infection (fungal, bacterial or viral) including human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (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.
  -  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. (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).
  -  Received anti-CD19 antibody-based therapy OR cytotoxic chemotherapy not described as maintenance therapy in inclusion #12 within 2 weeks of lymphodepletion.

Relevance to patient case: definitely relevant