Modified Immune Cells (Autologous iC9.GD2.CAR.IL-15 T cells) for Treating Patients with Relapsed or Refractory High Risk Neuroblastoma, Ganglioneuroblastoma, or Osteosarcoma

Inclusion Criteria

• Written Health Insurance Portability and Accountability Act (HIPAA) authorization signed by the subject if 18 years old or older, or by a legal guardian (if subject is <18 years old)
• Life expectancy >= 12 weeks
• Histological confirmation of neuroblastoma or ganglioneuroblastoma at initial diagnosis. Bone marrow samples are acceptable as confirmation of neuroblastoma OR confirmation of osteosarcoma at diagnosis
• High risk neuroblastoma with persistent/refractory or relapsed disease, defined as: * First or greater relapse of neuroblastoma following completion of aggressive multi-drug frontline therapy * First episode of progressive neuroblastoma during aggressive multi-drug frontline therapy * Persistent/refractory neuroblastoma as defined by less than a complete response (by the revised INRC) at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (such as A3973 or ANBL0532) * Patients must be diagnosed with high risk neuroblastoma at initial diagnosis or if non-high risk at time of initial diagnosis must have had evidence of metastatic progression when > 18 months of age OR relapsed or refractory osteosarcoma
• Measurable or evaluable disease per Revised International Neuroblastoma Response Criteria for subjects with neuroblastoma OR measurable disease by RECIST v1.1 criteria for subjects with osteosarcoma
• Adequate central nervous system function as defined by: * No known central nervous system (CNS) disease * No seizure disorder requiring antiepileptic drug therapy
• If clinically indicated, subject has been evaluated for brain metastases and either: * Does not have brain metastases OR * Does not have brain metastases that are clinically threatening as documented by the treating physician (no neurologic symptoms, no growth, no steroid requirement, no midline shift, no leptomeningeal carcinomatosis)
• Adequate cardiac function as defined by either a left ventricular ejection fraction (LVEF) ≥ 50% OR shortening fraction of ≥ 27% by echocardiogram, within 90 days of procurement
• Adequate pulmonary function as defined by no chronic oxygen requirement and room air pulse oximetry > 90%
• Females 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 or an intrauterine device that meets < 1% failure rate for protection from pregnancy in the product label
• Male subjects with female partners must have had a prior vasectomy, be willing to abstain from heterosexual activity 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, subject is willing and able to comply with study procedures
• PRIOR TO PROCUREMENT: Written informed consent to undergo cell procurement signed by legal guardian must be obtained prior to procurement. Written assent required as applicable for age 15-17 years old
• PRIOR TO PROCUREMENT: Adequate performance status as defined by Lansky or Karnofsky performance status of ≥ 60 (Lansky for < 16 years of age)
• PRIOR TO PROCUREMENT: Imaging and bone marrow study results from within 120 days prior to procurement to assess presence of active disease. Bone marrow studies are only relevant for neuroblastoma subjects.
• PRIOR TO PROCUREMENT: Subjects who have received murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA). Test can be pending at the time of cell procurement; only those patients with confirmed absence of HAMA will have cells generated.
• PRIOR TO PROCUREMENT: Hemoglobin >= 9.0 g/dL (obtained within 7 days of procurement) * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. Neuroblastoma (NB): Bone marrow involvement is only relevant to neuroblastoma subjects
• PRIOR TO PROCUREMENT: Absolute neutrophil count (ANC) >= 0.8 x 10^9/L (obtained within 7 days of procurement) * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
• PRIOR TO PROCUREMENT: Platelets (transfusion independent within 7 days of procurement) >= 50 x 10^9/L * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
• PRIOR TO PROCUREMENT: Maximum serum creatine (mg/dL) (within 72 hours) * Age 1 to < 2 years (=< 0.6 for male and =< 0.6 for female) * Age 2 to < 6 years (=< 0.8 for male and =< 0.8 for female) * Age 6 to < 10 years (=< 1 for male and =< 1 for female) * Age 10 to <13 years (=< 1.2 for male and =< 1.2 for female) * Age 13 to < 15 years (=< 1.6 for male and =< 1.6 for female) * Age 15 to < 18 years (=< 2.0 for male and =< 1.6 for female) * Age > 18 years (=< 2.2 for males and =< 1.6 for female) * Subjects with moderate impairment of renal function (normalized creatinine clearance 30-70 mL/min/1.73m^2) should have their fludarabine dose reduced by 20% and be monitored closely for excessive toxicity
• PRIOR TO PROCUREMENT: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 72 hours)
• PRIOR TO PROCUREMENT: Alanine aminotransferase (ALT) =< 500 U/L (within 72 hours)
• PRIOR TO PROCUREMENT: Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to cell procurement. NOTE: Premenarchal females do not require pregnancy testing
• PRIOR TO LYMPHODEPLETION: Written informed consent to enroll in the iC9.GD2.CAR.IL-15 cell therapy trial signed by legal guardian must be obtained prior to starting lymphodepletion. Written assent required as applicable for age 15-17 years old
• PRIOR TO LYMPHODEPLETION: Subjects with osteosarcoma must have baseline imaging performed within 14 days prior to lymphodepletion. Imaging studies must continue to show measurable disease by RECIST v 1.1 criteria and must be performed at least 3 weeks, or 5 half-lives (whichever is shorter), after completion of most recent therapy except radiation
• PRIOR TO LYMPHODEPLETION: Subject with neuroblastoma must have imaging AND bone marrow studies performed within 14 days prior to lymphodepletion. Imaging and/or bone marrow studies must continue to show measurable disease per Revised International Neuroblastoma Response Criteria and must be performed at least 3 weeks, or 5 half lives (whichever is shorter), after completion of most recent therapy except radiation. Results of bone marrow biopsies are required prior to start of lymphodepletion only if imaging does not exhibit measurable disease
• PRIOR TO LYMPHODEPLETION: Subject has not received investigational agent or cancer-directed therapy within the previous 3 weeks, or 5 half-lives (whichever is shorter), prior to prelymphodepletion imaging
• PRIOR TO LYMPHODEPLETION: Radiation therapy can be given at any point during the bridging time period but must be completed by approximately 7 days prior to pre-lymphodepletion imaging
• PRIOR TO LYMPHODEPLETION: Absolute neutrophil count (ANC) >= 0.8 x 10^9/L (within 72 hours) * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
• PRIOR TO LYMPHODEPLETION: Platelets (transfusion independent within 7 days) >= 50 x 10^9/L (within 72 hours) * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
• PRIOR TO LYMPHODEPLETION: Maximum serum creatine (mg/dL) * Age 1 to < 2 years (=< 0.6 for male and =< 0.6 for female) * Age 2 to < 6 years (=< 0.8 for male and =< 0.8 for female) * Age 6 to < 10 years (=< 1 for male and =< 1 for female) * Age 10 to <13 years (=< 1.2 for male and =< 1.2 for female) * Age 13 to < 15 years (=< 1.6 for male and =< 1.6 for female) * Age 15 to < 18 years (=< 2.0 for male and =< 1.6 for female) * Age > 18 years (=< 2.2 for male and =< 1.6 for female) ** Subjects with moderate impairment of renal function (normalized creatinine clearance 30-70 mL/min/1.73m^2) should have their fludarabine dose reduced by 20% and be monitored closely for excessive toxicity
• PRIOR TO LYMPHODEPLETION: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 72 hours)
• PRIOR TO LYMPHODEPLETION: ALT =< 500 U/L (within 72 hours)
• PRIOR TO LYMPHODEPLETION: Treatment with any tumor vaccines within the previous six weeks prior to lymphodepletion
• PRIOR TO LYMPHODEPLETION: Adequate performance status as defined by Lansky or Karnofsky performance status of >= 60 (Lansky for < 16 years of age)
• PRIOR TO LYMPHODEPLETION: Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to lymphodepletion. NOTE: Premenarchal females do not require pregnancy testing
• PRIOR TO LYMPHODEPLETION: Available autologous transduced activated T cells product meets the certificate of analysis
• PRIOR TO LYMPHODEPLETION: Subject has not received aldesleukin (IL-2) within 28 days of starting lymphodepletion
• PRIOR TO LYMPHODEPLETION: Subject has not received: * Filgrastim (granulocyte-colony stimulating factor [G-CSF]) (or biosimilar) within 7 days of starting lymphodepletion * Sargramostim (granulocyte-macrophage colony-stimulating factor [GM-CSF]) within 14 days of starting lymphodepletion * Pegfilgrastim within 21 days of starting lymphodepletion
• PRIOR TO LYMPHODEPLETION: Subject must not be receiving systemic corticosteroids at doses equivalent of ≥10mg prednisone daily or its equivalent; those receiving <10mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed * For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12 mg/m^2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10mg prednisone per day. Inhaled steroids are allowed * Systemic steroids must be stopped 48 hours prior to lymphodepletion and not used after infusion unless clinically required
• PRIOR TO LYMPHODEPLETION: Prior autologous stem cell transplant is allowed as long as it occurred >= 4 weeks prior to lymphodepletion
• PRIOR TO LYMPHODEPLETION: Prior therapeutic 131 iodine (I)-MIBG is allowed as long as it is completed >= 4 weeks prior to pre-lymphodepletion imaging
• PRIOR TO LYMPHODEPLETION: Prior anti-GD2 therapy (such as dinutuximab) is allowed as long as it is completed >= 4 weeks prior to pre-lymphodepletion imaging
• PRIOR TO LYMPHODEPLETION: Subject did not have major surgery within 14 days of starting lymphodepletion
• PRIOR TO LYMPHODEPLETION: Subjects that have received bridging therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion
• PRIOR TO LYMPHODEPLETION: Subject is not taking a prohibited or contraindicated medication prior to lymphodepletion. Contraindicated medications should be discontinued at least two weeks prior to the scheduled lymphodepletion or by at least 5 half-lives of the contraindicated medication, whichever is shorter
• PRIOR TO LYMPHODEPLETION: Subject does not have disease progression that would, in the opinion of the treating physician, place the subject at significant potential risk, such as location of lesion that would have high risk with tumor swelling (examples include airway or spinal canal)
• PRIOR TO LYMPHODEPLETION: No evidence of uncontrolled infection or sepsis
• PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Subject is a good candidate for treatment per investigator's discretion
• PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: No evidence of uncontrolled infection or sepsis
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subjects must not have received bridging therapy after their initial iC9.GD2.CAR.IL-15 cell infusion.
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Absolute neutrophil count (ANC) >= 0.8 x 10^9/L (within 72 hours) * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Platelets (transfusion independent within 7 days) >= 50 x 10^9/L (within 72 hours) * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Maximum serum creatine (mg/dL) (within 72 hours) * Age 1 to < 2 years (=< 0.6 for male and =< 0.6 for female) * Age 2 to < 6 years (=< 0.8 for male and =< 0.8 for female) * Age 6 to < 10 years (=< 1 for male and =< 1 for female) * Age 10 to <13 years (=< 1.2 for male and =< 1.2 for female) * Age 13 to < 15 years (=< 1.6 for male and =< 1.6 for female) * Age 15 to < 18 years (=< 2.0 for male and =< 1.6 for female) * Age > 18 years (=< 2.2 for male and =< 1.6 for female) ** Subjects with moderate impairment of renal function (normalized creatinine clearance 30-70 mL/min/1.73m^2) should have their fludarabine dose reduced by 20% and be monitored closely for excessive toxicity
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Aspartate aminotransferase (ALT) =< 500 U/L
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Adequate performance status as defined by Lansky or Karnofsky performance status of >= 60 (Lansky for < 16 years of age).
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to lymphodepletion. NOTE: Premenarchal females do not require pregnancy testing
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has not received: * Filgrastim (granulocyte-colony stimulating factor [G-CSF]) (or biosimilar) within 7 days of starting lymphodepletion * Sargramostim (granulocyte-macrophage colony-stimulating factor [GM-CSF]) within 14 days of starting lymphodepletion * Pegfilgrastim within 21 days of starting lymphodepletion
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject must not be receiving systemic corticosteroids at doses equivalent of ≥ 10mg prednisone daily or its equivalent; those receiving < 10mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed * For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12 mg/m^2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10mg prednisone per day. Inhaled steroids are allowed * Systemic steroids must be stopped 48 hours prior to lymphodepletion and not used after infusion unless clinically required
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject did not have major surgery within 14 days of starting lymphodepletion.
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject is not taking a prohibited or contraindicated medication prior to lymphodepletion. Contraindicated medications should be discontinued at least two weeks prior to the scheduled lymphodepletion or by at least 5 half-lives of the contraindicated medication, whichever is shorter.
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): No evidence of uncontrolled infection or sepsis.
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has completed the initial safety evaluation period without dose limiting toxicities (DLTs).
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has not experienced additional toxicity(ies) directly attributable to the initial T-cell infusion that would place them at excessive risk with re-infusion.
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has derived clinical benefit from the initial infusion as assessed by the investigator (stable disease or better to the initial infusion).
• PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has sufficient stored iC9.GD2.CAR.IL-15 T-cells for re-infusion.
• PRIOR TO SECOND INFUSION (OPTIONAL): Subject is a good candidate for treatment per investigator’s discretion.
• PRIOR TO SECOND INFUSION (OPTIONAL): No evidence of uncontrolled infection or sepsis.

Exclusion Criteria

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
• Has a known additional malignancy that is active and/or progressive requiring treatment
• History of hypersensitivity reactions to murine protein-containing products
• History of hypersensitivity to cyclophosphamide or fludarabine
• Current use of systemic corticosteroids at doses equivalent of ≥ 10mg prednisone daily or its equivalent; those receiving < 10mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed * For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12 mg/m2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10mg prednisone per day. Inhaled or topical steroids are allowed * Other than the above, systemic steroids must be stopped >14 days prior to procurement, but may be resumed after procurement if needed as per treating physician. Systemic steroids must be stopped 48 hours prior to lymphodepletion and not used after infusion unless clinically required
• Uncontrolled infection requiring systemic therapy
• Subjects are required to be negative for human immunodeficiency virus (HIV) antibody or HIV viral load, negative for hepatitis B surface antigen, or negative for hepatitis C virus (HCV) antibody or HCV viral load. 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
• For patients with relapsed or refractory osteosarcoma: exclude patients with rapidly progressive disease at the time of study entry, who have not been placed on bridging therapy, or do not have stable disease after prior treatment