Autologous IC9-CAR19 T cells in Treating Patients with Recurrent or Refractory Acute Lymphoblastic Leukemia

Inclusion Criteria

• CELL PROCUREMENT: Written informed consent for procurement signed by subject or legal guardian of a pediatric subject and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
• CELL PROCUREMENT: 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
• CELL PROCUREMENT: Karnofsky score > 60% if >= 16 years old or Lansky performance score of greater than 60% if < 16 years old
• CELL PROCUREMENT: Relapsed or refractory precursor B cell ALL: * Second or greater bone marrow relapse or central nervous system (CNS) OR * Any bone marrow relapse or CNS > 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 or CNS relapse with duration of first complete response (CR) < 1 year OR CR1 duration >= 1 year and refractory to >= 1 cycle of therapy for treatment of relapse * Subjects with isolated non-CNS extramedullary disease will be eligible as long as the time-of-remission criteria above for bone marrow and CNS relapses or primary refractory ALL are met and the biopsy for extramedullary disease confirms CD19 expression * For pediatric subjects: first bone marrow, CNS or isolated non-CNS extramedullary relapse refractory to 1 cycle of standard therapy for relapsed ALL * Subjects who have previously achieved remission with no detectible measurable residual disease (MRD) by multi-parameter flow cytometry, and who have redeveloped CD19+ MRD measured by multi-parameter flow cytometry will be eligible, provided that the duration of first MRD-negative clinical remission (CR) was < 1 year, MRD-negative first clinical remission (CR1) duration >= 1 year and refractory to >= 1 cycle of therapy for treatment of MRD recurrence, or MRD reappearance occurs during second or subsequent CR * Subjects who have persistent CD19+ MRD measured by multi-parameter flow cytometry after 3 cycles of initial chemotherapy, and have persistence of CD19+ MRD after one or more cycles of blinatumomab * CNS leukemia will be defined as definitive evidence of lymphoblasts in the cerebrospinal fluid at the time of screening OR residual radiographic findings (cranial nerve thickening, dural thickening or discrete parenchymal lesions) in patients with either lymphoblasts in the cerebrospinal fluid OR a tissue biopsy demonstrating leukemic infiltration of CNS or other tissue within 30 days prior to screening.
• CELL PROCUREMENT: Subjects with Philadelphia chromosome (Ph)+ ALL will be eligible if they have failed >= 2 ABL tyrosine kinase inhibitors, relapsed after allogeneic stem cell transplant, or have CD19+ MRD; 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
• CELL PROCUREMENT: CD19 positivity of lymphoblasts confirmed by flow cytometry or immunohistochemistry (IHC) per institutional standards
• CELL PROCUREMENT: Life expectancy >= 12 weeks
• CELL PROCUREMENT: Serum creatinine =< 1.5 x upper limit of normal (ULN), obtained within 72 hrs prior to procurement * For pediatric patients, adequate renal function is defined as below: ** Age: Maximum Serum Creatinine (mg/dL) ** 3 to < 6 years: =< 0.8 (male and female) ** 6 to < 10 years: =< 1 (male and female) ** 10 to < 13 years: =< 1.2 (male and female) ** 13 to < 16 years: =< 1.5 (male), =< 1.4 (female) ** 16 to < 18 years: =< 1.7 (male), =< 1.4 (female)
• CELL PROCUREMENT: Total bilirubin =< 1.5 x upper limit of normal (ULN), unless attributed to Gilbert’s syndrome, obtained within 72 hrs prior to procurement
• CELL PROCUREMENT: Aspartate aminotransferase (AST) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
• CELL PROCUREMENT: Alanine aminotransferase (ALT) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
• CELL PROCUREMENT: 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
• CELL PROCUREMENT: 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
• CELL PROCUREMENT: 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
• CELL PROCUREMENT: 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 systemic chemotherapy are defined as methotrexate =< 30 mg/m^2/week, mercaptopurine =< 100 mg/m^2/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; (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)
• CELL PROCUREMENT: Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• LYMPHODEPLETION: Written informed consent for the main study signed by subject or legal guardian of a pediatric subject
• LYMPHODEPLETION: Relapsed or refractory precursor B cell ALL, confirmed by presence of blasts in the blood or bone marrow (>= 5%) or in any extramedullary site; subjects who have previously achieved remission with no detectable measurable residual disease (MRD) by multiparameter flow cytometry, and who have re-developed CD19+ MRD measured by multiparameter flow cytometry are eligible, provided that the duration of first MRD-negative CR was < 1 year, MRD-negative CR1 duration >= 1 year and refractory to >= 1 cycle of therapy for treatment of MRD recurrence/relapse, or MRD-recurrence in second or subsequent morphologic CR; additionally, subjects who have persistent CD19+ MRD measured by multi-parameter flow cytometry after 3 cycles of initial chemotherapy, and have persistence of CD19+ MRD after one or more cycles of blinatumomab are eligible to participate. Because CNS leukemia is not curable with conventional therapies, subjects who met inclusion criterion for CNS leukemia at the time of procurement will be eligible for lymphodepletion even if intrathecal or systemic chemotherapy has rendered their cerebrospinal fluid free of lymphoblasts prior to lymphodepletion.
• LYMPHODEPLETION: Karnofsky score > 60% if >= 16 years old or Lansky performance score of greater than 60% if < 16 years old
• LYMPHODEPLETION: Life expectancy >= 12 weeks
• LYMPHODEPLETION: 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. Subjects who have received prior therapy with murine antibodies must have documentation of absence of HAMA within 8 weeks of lymphodepletion or after their most recent murine antibody therapy (whichever is shortest). For subjects that receive murine monoclonal antibodies between procurement and lymphodepletion, HAMA testing should be performed within 4 weeks prior to lymphodepletion and after the last monoclonal antibody dose
• LYMPHODEPLETION: Serum creatinine =< 1.5 x ULN, obtained within 72 hrs prior to lymphodepletion * For pediatric patients, adequate renal function is defined as below: ** Age: Maximum Serum Creatinine (mg/dL) ** 3 to < 6 years: =< 0.8 (male and female) ** 6 to < 10 years: =< 1 (male and female) ** 10 to < 13 years: =< 1.2 (male and female) ** 13 to < 16 years: =< 1.5 (male), =< 1.4 (female) ** 16 to < 18 years: =< 1.7 (male), =< 1.4 (female)
• LYMPHODEPLETION: Total bilirubin =< 1.5 x upper limit of normal (ULN) unless attributed to Gilbert’s syndrome, obtained within 72 hrs prior to procurement
• LYMPHODEPLETION: Aspartate aminotransferase (AST) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
• LYMPHODEPLETION: Alanine aminotransferase (ALT) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
• LYMPHODEPLETION: Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to lymphodepletion; 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
• LYMPHODEPLETION: 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
• LYMPHODEPLETION: 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
• LYMPHODEPLETION: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures
• LYMPHODEPLETION: For subjects who receive chemotherapy between cell procurement and lymphodepletion, washout periods between chemotherapy and the beginning of lymphodepletion will be required
• LYMPHODEPLETION: Subjects must have autologous transduced activated T-cells that meet the certificate of analysis (CofA) acceptance 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
• iC9-CAR19 CELL INFUSION: 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
• iC9-CAR19 CELL INFUSION: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: >= 18 years of age
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Karnofsky score > 60%
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Life expectancy >= 12 weeks
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Documentation of absence of human anti-mouse antibodies (HAMA), performed after the last iC9-CAR19 infusion
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Serum creatinine =< 1.5 x ULN (obtained within 72 hours prior to lymphodepletion)
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Total bilirubin =< 1.5 x ULN, unless attributed to Gilbert's syndrome (obtained within 72 hours prior to lymphodepletion)
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Aspartate aminotransferase (AST) =< 3.0 x ULN (obtained within 72 hours prior to lymphodepletion)
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Alanine aminotransferase (ALT) =< 3.0 x ULN (obtained within 72 hours prior to lymphodepletion)
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: 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 (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: 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
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: 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
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Subject meets at least one of the following criteria: * B-cell recovery (defined as absolute CD19+ cell count of > 50/uL in the blood or bone marrow CD19+ B cells >= 0.5% of marrow aspirate cells by flow cytometry) within 6 months of initial infusion; subjects who meet this criteria within 6 months of initial infusion may be started on lymphodepletion at a date later than 6 months from initial infusion * MRD positive (defined as >= 0.01% as assessed by multi-parameter flow cytometry) with CD19+ expression at any time after initial infusion
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: At least 4 weeks have passed since the initial iC9-CAR19 T cell infusion
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Subjects have resolved/recovered symptoms from CRS and/or ICANS that developed after prior iC9-CAR19 T cell infusion
• PRIOR TO LYMPHODEPLETION FOR THE SECOND INFUSION: Subjects must have autologous transduced activated T cells that meet the Certificate of Analysis (CofA) acceptance criteria; the subject must have sufficient available cells or have sufficient stored peripheral blood to manufacture additional iC9-CAR19 T cells
• SECOND 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
• SECOND iC9-CAR19 CELL INFUSION: 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
• SECOND iC9-CAR19 CELL INFUSION: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures

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
• CELL PROCUREMENT: Subjects with CNS leukemia with ongoing progression of neurologic symptoms will be excluded. Intrathecal chemotherapy will be allowed to continue between cell procurement and lymphodepleting chemotherapy
• CELL PROCUREMENT: 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)
• CELL PROCUREMENT: Subjects must not have tumor in a location where enlargement could cause airway obstruction
• CELL PROCUREMENT: Subjects may not have an oxygen requirement as defined by pulse oximetry of < 90% on room air
• CELL PROCUREMENT: Subjects must not have left ventricular ejection fraction of < 40% (shortening fraction < 27% for pediatric subjects) as measured by echocardiogram or multi-gated acquisition (MUGA)
• CELL PROCUREMENT: Patients with the following systemic viral infections will be excluded: active human immunodeficiency virus (HIV), 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 not be positive for HIV antibody or HIV viral load, negative for hepatitis B surface antigen, or negative for HCV antibody or HCV viral load
• CELL PROCUREMENT: Patients who are on treatment for other active uncontrolled infections (not referenced above) with resolution of signs/symptoms are not excluded; non-influenza, non-respiratory syncytial virus (RSV), isolated upper respiratory infections are not excluded; other active uncontrolled infections will be excluded
• CELL PROCUREMENT: 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) * Physiologic replacement with hydrocortisone is allowed at doses 6-12 mg/m^2/day, or equivalent
• CELL PROCUREMENT: Received anti-CD19 antibody-based therapy OR cytotoxic chemotherapy not described as maintenance therapy within 2 weeks of procurement
• 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)
• LYMPHODEPLETION: Subjects must not have tumor in a location where enlargement could cause airway obstruction
• LYMPHODEPLETION: Subjects may not have an oxygen requirement as defined by pulse oximetry of < 90% on room air
• LYMPHODEPLETION: Treatment with any investigational drug within 14 days (ie, two weeks) prior to lymphodepletion or has received any tumor vaccines within the previous five weeks prior to lymphodepletion
• LYMPHODEPLETION: Subject has received pegylated-asparaginase =< 3 weeks prior to lymphodepletion
• LYMPHODEPLETION: Radiotherapy to a non-CNS site completed <1 week prior to lymphodepletion, or CNS directed radiation completed < 7 weeks prior to lymphodepletion
• LYMPHODEPLETION: Subject is receiving following drugs < 1 week prior to lymphodepletion: salvage chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 mg/m^2, anthracyclines, cyclophosphamide, methotrexate >= 25 mg/m^2)
• LYMPHODEPLETION: Any systemic drug used for graft versus host disease (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)
• LYMPHODEPLETION: 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/m^2, cytosine arabinoside < 100 mg/m^2/day, and asparaginase (non-pegylated); these drugs should not be administered concomitantly or following lymphodepleting chemotherapy
• LYMPHODEPLETION: CNS prophylaxis or treatment for CNS leukemia with intrathecal methotrexate, cytarabine and/or hydrocortisone treatment must be stopped prior to lymphodepleting chemotherapy
• LYMPHODEPLETION: Patients with the following systemic viral infections will be excluded: active HIV, HBV, HCV; note: To meet eligibility subjects are required to be negative for HIV antibody or HIV viral load, negative for hepatitis B surface antigen, or negative for HCV antibody or HCV viral load
• LYMPHODEPLETION: 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
• LYMPHODEPLETION: Use of systemic corticosteroids at doses >= 10mg/day prednisone or its equivalent; those receiving < 10 mg/day may be enrolled at discretion of investigator; (Note: Corticosteroid use with doses at the discretion of the treating physician are allowed after procurement up to the beginning of lymphodepletion) * Physiologic replacement with hydrocortisone is allowed at 6-12 mg/m^2/day, or equivalent
• iC9-CAR19 CELL INFUSION: Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary e.g., to treat CRS)
• iC9-CAR19 CELL INFUSION: Severe systemic uncontrolled disease or toxicities that develop after lymphodepletion may prompt exclusion from cell infusion at the discretion of the investigator
• iC9-CAR19 CELL INFUSION: Received any donor lymphocyte infusions (DLI) =< 6 weeks prior to iC9-CAR19 T cell product administration
• iC9-CAR19 CELL INFUSION: 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)
• LYMPHODEPLETION FOR THE SECOND INFUSION: 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)
• LYMPHODEPLETION FOR THE SECOND INFUSION: 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
• LYMPHODEPLETION FOR THE SECOND INFUSION: Subjects with a tumor in a location where enlargement could cause airway obstruction
• LYMPHODEPLETION FOR THE SECOND INFUSION: Subjects with an oxygen requirement as defined by pulse oximetry of < 90% on room air
• LYMPHODEPLETION FOR THE SECOND INFUSION: Subjects with an active uncontrolled infection. Subjects who are on treatment an active uncontrolled infections with resolution of signs/symptoms are not excluded; non-influenza, non-human respiratory syncytial virus (RSV), isolated upper respiratory infections are not excluded;
• LYMPHODEPLETION FOR THE SECOND INFUSION: Use of systemic corticosteroids at doses >= 10 mg/day prednisone or its equivalent; those receiving < 10 mg/day may be enrolled at discretion of investigator; (note: corticosteroid use with doses at the discretion of the treating physician are allowed after procurement up to the beginning of lymphodepletion.) * Physiologic replacement with hydrocortisone is allowed at 6-12 mg/m^2/day, or equivalent
• SECOND iC9-CAR19 CELL INFUSION: Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary (e.g., to treat CRS)
• SECOND iC9-CAR19 CELL INFUSION: Severe systemic uncontrolled disease or toxicities that develop after lymphodepletion may prompt exclusion from cell infusion at the discretion of the investigator